Ventricle Weight Research Articles

Cinaciguat (BAY-582667) Modifies Cardiopulmonary and Systemic Circulation in Chronically Hypoxic and Pulmonary Hypertensive Neonatal Lambs in the Alto Andino.

Neonatal pulmonary hypertension (NPHT) is produced by sustained pulmonary vasoconstriction and increased vascular remodeling. Soluble guanylyl cyclase (sGC) participates in signaling pathways that induce vascular vasodilation and reduce vascular remodeling. However, when sGC is oxidized and/or loses its heme group, it does not respond to nitric oxide (NO), losing its vasodilating effects. sGC protein expression and function is reduced in hypertensive neonatal lambs. Currently, NPHT is treated with NO inhalation therapy; however, new treatments are needed for improved outcomes. We used Cinaciguat (BAY-582667), which activates oxidized and/or without heme group sGC in pulmonary hypertensive lambs studied at 3,600 m. Our study included 6 Cinaciguat-treated (35 ug kg−1 day−1 x 7 days) and 6 Control neonates. We measured acute and chronic basal cardiovascular variables in pulmonary and systemic circulation, cardiovascular variables during a superimposed episode of acute hypoxia, remodeling of pulmonary arteries and changes in the right ventricle weight, vasoactive functions in small pulmonary arteries, and expression of NO-sGC-cGMP signaling pathway proteins involved in vasodilation. We observed a decrease in pulmonary arterial pressure and vascular resistance during the acute treatment. In contrast, the pulmonary pressure did not change in the chronic study due to increased cardiac output, resulting in lower pulmonary vascular resistance in the last 2 days of chronic study. The latter may have had a role in decreasing right ventricular hypertrophy, although the direct effect of Cinaciguat on the heart should also be considered. During acute hypoxia, the pulmonary vascular resistance remained low compared to the Control lambs. We observed a higher lung artery density, accompanied by reduced smooth muscle and adventitia layers in the pulmonary arteries. Additionally, vasodilator function was increased, and vasoconstrictor function was decreased, with modifications in the expression of proteins linked to pulmonary vasodilation, consistent with low pulmonary vascular resistance. In summary, Cinaciguat, an activator of sGC, induces cardiopulmonary modifications in chronically hypoxic and pulmonary hypertensive newborn lambs. Therefore, Cinaciguat is a potential therapeutic tool for reducing pulmonary vascular remodeling and/or right ventricular hypertrophy in pulmonary arterial hypertension syndrome.

Pirfenidone attenuates cardiac hypertrophy against isoproterenol by inhibiting activation of the janus tyrosine kinase-2/signal transducer and activator of transcription 3 (JAK-2/STAT3) signaling pathway

ABSTRACT Cardiovascular risk factors have attracted increasing attention in recent years with the acceleration of population aging, amongst which cardiac hypertrophy is the initiating link to heart failure. Pirfenidone is a promising agent for the treatment of idiopathic pulmonary fibrosis and has recently proven to exert inhibitory effects on the inflammatory response. This study proposes to explore the potential pharmacological action of pirfenidone in treating cardiac hypertrophy in a rodent model. Four groups of mice were used in the present study: the control, ISO (5 mg/kg/day) for 7 days, pirfenidone (200 mg/kg/day) for 14 days, and spironolactone (SPI) (200 mg/kg/day) for 14 days groups. Increased heart weight index, left ventricle (LV) weight index, LV wall thickness, declined LV volume, and elevated serum levels of CK-MB, AST, and LDH were observed in ISO-challenged mice, all of which were dramatically reversed by the administration of pirfenidone or SPI. Furthermore, an elevated cross-sectional area of cardiomyocytes in the wheat germ agglutinin (WGA) staining of heart cross-sections, upregulated atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-Myosin Heavy Chain (β-MHC), and excessively released tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) in cardiac tissues were observed in the ISO group but greatly alleviated by pirfenidone or SPI. Lastly, the promoted expression levels of p-JAK-2/JAK-2 and p-STAT3/STAT-3 in the cardiac tissues of ISO-challenged mice were significantly repressed by pirfenidone or SPI. Collectively, our data reveals a therapeutic property of pirfenidone on ISO-induced cardiac hypertrophy in mice.

Characterization of the spontaneous right ventricular hypertrophy and evolution to heart failure in Wistar Kyoto rat strain

Heart failure is a pathological condition that remains as a major cause of morbi‐mortality in the world, and several cellular mechanisms involved in the development of heart failure remain unknown. In this study it was characterized a spontaneous experimental model of right ventricular hypertrophy from Wistar Kyoto rat strain and monocrotaline injection as a factor to induce the development of heart failure. Morphological and functional cardiovascular parameters, and atrial natriuretic factor (ANF) in serum were measured to determine criteria to be considered as a model of heart failure. Male WK rats 2 months old were assigned to 3 experimental groups (n=8 each group): control, right ventricular hypertrophy + saline (RVH+S) and right ventricular hypertrophy + monocrotaline (RVH+MCT). RVH was diagnosed through no invasive electrocardiographic record in awake animals, and one dose of monocrotaline (60 mg/Kg, ip) was injected. After 3 weeks, cardiovascular parameters were recorded (systemic and pulmonary systolic arterial blood pressure, heart rate), and arterial blood from aorta was taken and the heart was removed and analyzed. Total heart, right ventricle, left ventricle weights (g), and right ventricle free wall (in mm) were significantly different in the RVH+S (1.3±0.02, 0.40±14.11, 0.58±13, 2.86±0.19) and the RVH+MCT (1.6±0.09, 0.53±17.5, 0.67±18.94, 4±0.32) groups in comparison with the control group (0.99±0.04, 0.22±4.0, 0.55±14.38, 2.13±0.05), P>0.001 for all parameters, except for LV weight in the RVH+S group. The systemic arterial blood pressure analysis demonstrates absence of significant difference between groups, however, right ventricular pressure (RVP in mm Hg) in the RVH+S (42±2.53), and RVH+MCT (78±4.22), was significantly increased in comparison with the control group (22±1.16), P<0.001. ANF levels in serum were higher in the RVH+S and RVH+MCT experimental groups in comparison with the control group (537±11.04, 557±7.7 and 473±10.65 in pg/ml, respectively; P<0.01). The results suggest that a sub‐strain from WK rats develop right ventricular hypertrophy spontaneously and with the administration of monocrotaline, severe right and left ventricular hypertrophy was developed, changes associated to an increase in levels of atrial natriuretic peptide suggesting heart failure, then could be a useful experimental model of heart failure where right ventricular hypertrophy is a central pathologic mechanism.

Astaxanthin attenuates cardiovascular dysfunction associated with deoxycorticosterone acetate-salt-induced hypertension in rats

ABSTRACT Background Hypertension is a major global health problem. It is a major risk factor of cardiovascular disease. One of the most used experimental models in studying antihypertensive action is the deoxycorticosterone acetate (DOCA)-salt hypertensive rat. This study aimed to investigate the cardiovascular protective effect of astaxanthin (ASX) in DOCA-salt-induced hypertension and its possible underlying mechanisms. Methods A total of 48 adult male Wistar albino rats were divided into three groups: control, DOCA, and DOCA + ASX. Blood pressure, serum cardiac enzyme levels, some oxidative stress and inflammatory biomarker levels, and lipid profile levels were measured. The weight of the left ventricle to tibial length ratio was calculated. Apoptosis detection and total genomic DNA extraction in aortic and cardiac tissues were investigated. The apoptotic marker BAX was also immunohistochemically assessed in the heart and aorta. Results Compared to the control group, the DOCA group was associated with a significant increase in blood pressure, serum cardiac enzyme levels, oxidative stress and inflammatory biomarker levels, lipid profile except serum high-density lipoprotein (HDL), weight of the left ventricle to tibial length, and total released DNA fragmentation level of the left ventricle and aorta and a significant decrease in reduced glutathione (GSH) and HDL. Compared to the DOCA group, the DOCA + ASX group significantly improved the DOCA-induced changes. Conclusion ASX has beneficial protective effects on DOCA-salt-induced hypertension via DNA fragmentation protection, apoptosis inhibition, antioxidant, anti-inflammatory, and its effects on lipid levels.

NaHCO3, L-arginine, and vitamin C supplemented vegetable diet ameliorates tachycardia and polycythemia in the broiler chicken.

The study aimed to investigate if vegetable-based high-energy mash diets supplemented with NaHCO3, L-arginine + vitamin C, and vegetable oils were effective against tachycardia and polycythemia in the broiler chicken. A total of 256 Ross-308day-old male broiler chicks were randomly distributed into eight dietary treatment groups in a three-way ANOVA with 2 × 2 × 2 factorial arrangement (three factors, i.e., NaHCO3, L-arginine + vitamin C, and vegetable oil each with two levels, e.g., 0 and 0.1% of NaHCO3 and L-arginine + vitamin C; 3 and 4% of vegetable oil supplemented with basal diet) for a period of 35days. Iso-caloric and iso-nitrogenous diets were formulated and supplied ad libitum. The final live weight (FLW), average daily feed intake (ADFI), average daily gain (ADG), feed efficiency (FE), carcass traits, cardio-pulmonary morphometry, total protein (TP), hemoglobin (Hb), triiodothyronine (T3), incidence of tachycardia, and polycythemia were examined. Supplementation of NaHCO3 increased 2.2% ADFI, 5.5% FE, and 23.2% TP. The L-arginine + vitamin C increased 2.4% FLW and decreased 1.9% heart rate. Vegetable oil increased 1.3% ADFI, 4.2% ADG, 8.6% FE, 23.1% Hb, and 15.5% PCV. The NaHCO3, L-arginine + vitamin C, and vegetable oil additively interacted to increase 31.5% T3 at the expense of 21.1% of the weight of the right ventricle (RV). The RV:TV, carcass traits, and hemato-biochemical indices remained within normal range irrespective of the levels of the supplementations of the test ingredients. It was concluded that vegetable-based high-energy mash diets were not susceptible to tachycardia and polycythemia. The addition of NaHCO3 and L-arginine + vitamin C ameliorated the propensity of tachycardia and polycythemia without deteriorating performance, carcass traits, and hemato-biochemical indices of the broiler chicken in a dose-dependent manner.

Morphological and morphometrical characteristics of cattle heart structure

The paper presents the results of macro- and microscopic structure of cattle heart on the organ-, tissue- and cell levels. The samples of the selected material (n = 5) were preserved in a 10–12 % water solution of neutral formaline with its further charging into wax. Histologic sections not more than 10 mkm were made from wax blocks by using a sliding microtome MC-2. Hematoxilin- and eosin staining of histological sections by Heydengine technique was used for studying cell morphology, carrying out morphometrical studies and for receiving review samples. Histoarchitecture of the structural parts of the heart (ventricle and auricle) and their morphometrical parameters were studied on the histological preparations using the light microscopy technique. The experimantal part of the scientific research was carried out in compliance with the requirements of “European Convention for the Protection of Vertebrate Animals used for Experimantal and other Scientific Purposes” (Strussburg, 1986). The cattle heart is located in a thorax between two lungs, in front of a diaphragm and shifted left. In the 3rd–4th rib region the heart adjacents to a thoracic wall. The heart apex is in the 5th rib region. The absolute weight of a cattle heart equals 2143.27 ± 38.76 g, the relative weight equals – 0.43 ± 0.006 %. The net weight of the heart without the epicardial fat equals 1926.12 ± 31.12 g. Herewith, the weight of the aortic ventricle equals 978.54 ± 19.52 g, the weight of the pulmonic ventricle equals 554.17 ± 14.21 g, the weight of both ventricles equals 1539.08 ± 49.74 g. The auricles weight was the least and equaled 397.18 ± 11.21 g. The ratio of the ventricle weight of the heart to its net weight equals 1:0.2, and the ratio of the weight of the auricle myocard to the weight of the ventricle myocard equals 1:0.26. The heart height equaled 23.08 ± 0.11 сm, width – 13.9 ± 0.18 cm and the circumference – 38.08 ± 0.9 cm. According to the analysis of such liniar measurements, the cattle heart in the animals of the experimental group is characterized as that of an enlarged- and short form. The heart wall consists of three sacs – endocardium, myocard and epicardium. The dominating weight of the heart wall is in a muscular layer (myocard), which consists of transversus stripe muscular fibers which are formed on the basis of mononuclear cells – cardiomyocytes which are interlinked into muscular fibers. According to the cytometric analysis of cardiomyocytes, their largest volume – (11225.73 ± 824.42 mkm3) is observed in the aortic ventricle, smaller – (7963.60 ± 627.09 mkm3) – in a pulmonic ventricle and the smallest – (5361.60 ± 583.91 mkm3) in the auricle cardiomyocytes. Herewith, the volumes of cardiomyocytes nuclei in an aortic ventricle (124.55 ± 7.99 mkm3 and in a pulmonuc ventricle (121.67 ± 7.02 mkm3) are nearly the same, and in the auricle cardiomyocytes the nuclei volume is significantly smaller and it equals 101.05 ± 6.04 mkm3 respectively. Such morphometrical parameters of cardiomyocytes and their nuclei are evidenced in their nuclei-cytoplasmatic ratio, which is the smallest in the cardiomyocytes of an aortic ventricle – 0.0113 ± 0.0068, somewhat larger in a pulmonic ventricle – 0.0156 ± 0.0054 and the largest – 0.0234± 0.0058 in the auricle cardiomyocytes, that is connected with the special properties of the muscular tissue of a myocard which is capable of spontaneous rythmic beatings depending on their morphofunctional load: the ventricles pump the blood from the heart to the body performing the gratest load (the aortic ventricle acts a s a pump, and the pulmonic ventricle acts as a container), the auricles receive the blood which returns to the heart from the animal body, performing somewhat smaller load.

The co-administration effects of florfenicol and lasalocid on performance, biochemical and pathological parameters of muscle, heart, liver, kidney and sciatic nerve in broiler chickens.

The study aimed to examine the effect of simultaneous application of florfenicol and lasalocid on the performance and vital organ function of chickens. For this, 300 chicks were divided into four groups. Group one to three received florfenicol, lasalocid and lasalocid plus florfenicol, respectively. Group four as the control group received a basic diet without lasalocid or florfenicol. Lasalocid was used from 7 to 35 days old, continuously. Florfenicol was used at 21 days old for 5 days. The growth indices were measured at the end of each week. The chickens were euthanized at the ages of 28 and 35 days old after collecting blood samples with and without anticoagulants. The liver, heart, muscle, kidney and sciatic nerve were collected in formalin 10% for histopathological examination. The blood and serum samples were used to determine clinical pathologic and hematologic indices. The ratio of internal organs to body weight and ratio of the right ventricle to the total ventricles (RV/TV) of the heart was measured. Results showed, the use of lasalocid decreased feed conversion rate and triglyceride, and increased total protein. Simultaneous administration of lasalocid and florfenicol affected histopathology of the liver and heart and significantly increased creatine phosphokinase, uric acid and the ratio of RV/TV of heart. The eosinophil percentage in the chickens who received florfenicol plus lasalocid was significantly higher than chickens who received florfenicol alone (p < 0.05). In conclusion, it seems that simultaneous administration of the florfenicol and lasalocid induces side‐effects especially on cardiac function and it is not recommended.

Saskatoon berry supplementation prevents cardiac remodeling without improving renal disease in an animal model of reno-cardiac syndrome.

Saskatoon berry (SKB) may have the potential to counter reno-cardiac syndrome owing to its antioxidant capacity. Here, we investigated the renal and cardiovascular effects of SKB-enriched diet in a rat model of reno-cardiac disease. Two groups of wild-type rats (+/+) and two groups of Hannover Sprague-Dawley (Han:SPRD-Cy/+) rats were given either regular diet or SKB diet (10% w/w total diet) for 8weeks. Body weight, kidney weight, kidney water content, and left ventricle (LV) weight were measured. Blood pressure (BP) was measured by the tail-cuff method. Echocardiography was performed to assess cardiac structure and function. Serum creatinine and malondialdehyde (MDA) were also measured. Han:SPRD-Cy/+ rats had significantly higher kidney weight, kidney water content, LV weight, BP, and creatinine compared with wild-type rats (+/+). The SKB diet supplementation did not reduce kidney weight, kidney water content, BP, and LV weight in Han:SPRD-Cy/+ rats. The SKB diet also resulted in higher systolic BP in Han:SPRD-Cy/+rats. Han:SPRD-Cy/+rats showed cardiac structural remodeling (higher LV wall thickness) without any cardiac functional abnormalities. Han:SPRD-Cy/+ rats also had significantly higher creatinine whereas the concentration of MDA was not different. The SKB diet supplementation reduced cardiac remodeling and the concentration of MDA without altering the concentration of creatinine in Han:SPRD-Cy/+ rats. In conclusion, Han:SPRD-Cy/+ rats developed significant renal disease, high BP, and cardiac remodeling by 8weeks without cardiac functional impairment. The SKB diet may be useful in preventing cardiac remodeling and oxidative stress in Han:SPRD-Cy/+rats. PRACTICAL APPLICATIONS: Saskatoon berry (SKB) is widely consumed as fresh fruit or processed fruit items and has significant commercial value. It may offer health benefits due to the presence of bioactives such as anthocyanins. SKB has very good culinary flavors, and it is an economically viable fruit crop in many parts of the world. The disease-modifying benefits of SKB are mainly ascribed to the antioxidant nature of its bioactive content. Polycystic kidney disease is a serious condition that can lead to renal and cardiac abnormalities. Here, we showed that SKB supplementation was able to mitigate cardiac remodeling and lower the level of a marker of oxidative stress in an animal model of reno-cardiac syndrome. Our study suggests that SKB possesses beneficial cardioprotective properties. Further evidence from human studies may help in increasing the consumption of SKB as a functional food.

8-Gingerol Ameliorates Myocardial Fibrosis by Attenuating Reactive Oxygen Species, Apoptosis, and Autophagy via the PI3K/Akt/mTOR Signaling Pathway.

8-gingerol (8-Gin) is the series of phenolic substance that is extracted from ginger. Although many studies have revealed that 8-Gin has multiple pharmacological properties, the possible underlying mechanisms of 8-Gin against myocardial fibrosis (MF) remains unclear. The study examined the exact role and potential mechanisms of 8-Gin against isoproterenol (ISO)-induced MF. Male mice were intraperitoneally injected with 8-Gin (10 and 20 mg/kg/d) and concurrently subcutaneously injected with ISO (10 mg/kg/d) for 2 weeks. Electrocardiography, pathological heart morphology, myocardial enzymes, reactive oxygen species (ROS) generation, degree of apoptosis, and autophagy pathway-related proteins were measured. Our study observed 8-Gin significantly reduced J-point elevation and heart rate. Besides, 8-Gin caused a marked decrease in cardiac weight index and left ventricle weight index, serum levels of creatine kinase and lactate dehydrogenase (CK and LDH, respectively), ROS generation, and attenuated ISO-induced pathological heart damage. Moreover, treatment with 8-Gin resulted in a marked decrease in the levels of collagen types I and III and TGF-β in the heart tissue. Our results showed 8-Gin exposure significantly suppressed ISO-induced autophagosome formation. 8-Gin also could lead to down-regulation of the activities of matrix metalloproteinases-9 (MMP-9), Caspase-9, and Bax protein, up-regulation of the activity of Bcl-2 protein, and alleviation of cardiomyocyte apoptosis. Furthermore, 8-Gin produced an obvious increase in the expressions of the PI3K/Akt/mTOR signaling pathway-related proteins. Our data showed that 8-Gin exerted cardioprotective effects on ISO-induced MF, which possibly occurred in connection with inhibition of ROS generation, apoptosis, and autophagy via modulation of the PI3K/Akt/mTOR signaling pathway.

Empagliflozin Inhibits Proximal Tubule NHE3 Activity, Preserves GFR, and Restores Euvolemia in Nondiabetic Rats with Induced Heart Failure.

SGLT2 inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. Experiments with nondiabetic HF rats tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) inhibits proximal tubule (PT) NHE3 activity and improves renal salt and water handling. Male Wistar rats were subjected to myocardial infarction or sham operation. After 4 weeks, rats that developed HF and sham rats were treated with EMPA or untreated for an additional 4 weeks. Immunoblotting and quantitative RT-PCR evaluated SGLT2 and NHE3 expression. Stationary in vivo microperfusion measured PT NHE3 activity. EMPA-treated HF rats displayed lower serum B-type natriuretic peptide levels and lower right ventricle and lung weight to tibia length than untreated HF rats. Upon saline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment prevented GFR decline and renal atrophy in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 protein and mRNA abundance were upregulated in the PT of HF rats. Prevention of HF progression by EMPA is associated with reduced PT NHE3 activity, restoration of euvolemia, and preservation of renal mass. Moreover, dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF.

Androgens and Diet Regulation of SARS‐CoV‐2 Viral Entry Proteins: Implications for COVID‐19 Cardiorenal Outcomes Severity in Polycystic Ovary Syndrome

BackgroundThe susceptibility and the severity of coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) are associated with hyperandrogenism, obesity, and pre‐existing pulmonary, metabolic, renal or cardiac conditions. Hyperandrogenemia and ovarian dysfunction characterize polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women. Women with PCOS have higher prevalence of obesity and higher incidence of cardiovascular diseases and renal injury, making them a population at risk for severe COVID‐19 outcomes.MethodsThree‐week‐old female mice were implanted with Silastic tubes filled with the nonaromatizable androgen dihydrotestosterone (DHT, 8 mg) or vehicle (empty tubes). Animals were maintained on high‐fat diet (HFD; 60% kcal fat) or low‐fat diet (LFD; 10% kcal fat, sucrose‐matched) for 90 days. Fat mass (EchoMRI), kidney and left ventricle (LV) weights as well as the cardiac and renal expression of the inflammatory markers interleukin‐6 (IL‐6), tumor necrosis factor‐α (TNF‐α), and interleukin‐1β (IL‐1β) were assessed. Moreover, circulatory, urinary, renal and cardiac levels of SARS‐CoV‐2 host cell receptor angiotensin converting enzyme 2 (ACE2) were quantified. Additionally, renal and cardiac mRNA and protein expression of the multiple cellular proteases required for viral entry (TMPRSS2, TMPRSS4, furin, cathepsin L, and ADAM17) were assessed.ResultsHFD exacerbated DHT‐mediated increases in fat mass (20.28 ± 1.10 vs. 6.78 ± 0.43 g, p<0.05), kidney weight (33.79 ± 1.35 vs. 26.52 ± 1.08 g, p<0.05), LV hypertrophy (7.48 ± 0.21 vs. 6.41 ± 0.28 g, p<0.05) and renal and cardiac expression of the inflammatory marker IL‐6 (1.5 and 2.5‐fold, respectively). PCOS mice on both diets showed higher urinary ACE2 (LFD: 18‐fold, HFD: 10‐fold) and altered renal mRNA and/or protein expression of all the measured targets. DHT upregulated renal TMPRSS2 (1.19 ± 0.04 vs. 0.98 ± 0.03 AU, p<0.05) and cathepsin L (2.64 ± 0.25 vs. 0.62 ± 0.25 AU, p<0.05) proteins in HFD‐fed DHT‐treated mice compared to LFD‐fed DHT‐treated mice. In the heart, LFD‐fed DHT‐treated mice showed no change in ACE2 and the cellular proteases on either the mRNA or protein levels except for ADAM17 protein that was significantly upregulated (1.63‐fold) compared to the vehicle‐treated group. On the other hand, while HFD‐fed DHT‐treated mice showed similar increase in cardiac ADAM17 protein (1.64‐fold vs. LFD‐fed vehicle‐treated), they showed higher mRNA expression of ACE2 (1.83‐fold) and furin (1.32‐fold) compared to the HFD‐fed vehicle‐treated mice.Conclusion and significanceOur findings highlight women with PCOS as a population with a high risk of COVID‐19 associated cardiac and renal complications. Further, our study suggests dietary control recommendations for optimal management of women with PCOS that can ultimately attenuate COVID‐19 cardiorenal outcomes.

Cichorium intybus Inhibits Doxorubicin- Induced Myocardial fibrosis in Wistar Rats Via Inflammatory Markers and Collagen Repression

Many allopathic medicines demand to remedy for myocardial fibrosis but fail to fulfill the purpose, because of side effects and high cost. Herbal medicine has fewer side effects and natural herbs are considered safe when compared with synthetic medicines. The present study aimed to study the effect of extract of Cichorium intybus on experimentally induced myocardial fibrosis in Wistar rats. The objective of the present study was to find out the possibilities of the use of Cichorium intybus as a supportive/ protective medicine and to explore the possible toxicities of Cichorium intybus in these models. Myocardial fibrosis was induced by Doxorubicin (2.5 mg/kg, i.p. Thrice a week) rats. Blood pressure, Collagen levels, Left ventricle weight index were effectively reduced in animal groups treated with the extract. The effect of extracts was studied on various oxidative stress markers like SOD, CAT, LOP, and NO. Extract of Cichorium intybus was shown significantly decreased in blood pressure and significantly shows the antioxidant effect when compared to the hypertensive control group.

Cardiac response to adrenergic stress differs by sex and across the lifespan.

The aging heart is well-characterized by a diminished responsiveness to adrenergic activation. However, the precise mechanisms by which age and sex impact adrenergic-mediated cardiac function remain poorly described. In the current investigation, we compared the cardiac response to adrenergic stress to gain mechanistic understanding of how the response to an adrenergic challenge differs by sex and age. Juvenile (4 weeks), adult (4-6 months), and aged (18-20 months) male and female mice were treated with the β-agonist isoproterenol (ISO) for 1 week. ISO-induced morphometric changes were age- and sex-dependent as juvenile and adult mice of both sexes had higher left ventricle weights while aged mice did not increase cardiac mass. Adults increased myocyte cell size and deposited fibrotic matrix in response to ISO, while juvenile and aged animals did not show evidence of hypertrophy or fibrosis. Juvenile females and adults underwent expected changes in systolic function with higher heart rate, ejection fraction, and fractional shortening. However, cardiac function in aged animals was not altered in response to ISO. Transcriptomic analysis identified significant differences in gene expression by age and sex, with few overlapping genes and pathways between groups. Fibrotic and adrenergic signaling pathways were upregulated in adult hearts. Juvenile hearts upregulated genes in the adrenergic pathway with few changes in fibrosis, while aged mice robustly upregulated fibrotic gene expression without changes in adrenergic genes. We suggest that the response to adrenergic stress significantly differs across the lifespan and by sex. Mechanistic definition of these age-related pathways by sex is critical for future research aimed at treating age-related cardiac adrenergic desensitization.

POTENTIAL ROLE OF GLP-1 RECEPTOR AGONIST IN A RAT MODEL OF CARDIO-RENAL SYNDROME TYPE-3: EFFECTS ON OXIDATIVE, INFLAMMATORY AND INOS EXPRESSION AXIS

Background: Acute renal and cardiac diseases are common encounters in hospitalized and non-hospitalized patients. Kidney and heart pathology are continuously interrelated. The impact of acute kidney injury (AKI) on the cardiac function is demonstrated in both preclinical and clinical studies and is termed cardio-renal syndrome type 3.Aim of the work: The aim of this work is to establish an animal model of cardio-renal syndrome type 3, and to study the effect of glucagon-like peptide-1 receptor (GLP-1R) agonist “liraglutide” on this condition.Materials and methods: Sixty male Wistar rats were used in this study and were divided into six groups (10 per group). Group 1: control, Group 2: low dose liraglutide-treated rats(L-lira). Group 3: high dose liraglutide-treated rats (H-lira). Group 4: Gentamicin (GM) treated rats. Group 5: low dose liraglutide- and GM-treated rats (L-lira-GM). Group 6: high dose liraglutide- and GM-treated rats (H-lira-GM). Liraglutide was given daily by subcutaneous injection for three weeks. GM was injected intraperitoneally (IP) starting from day 15 to day 21.Results: GM treatment was associated with histopathological injuries of both renal and cardiac tissues, in addition to significant elevation of renal biomarkers (serum urea and creatinine) as well as cardiac biomarkers (cardiac troponin I (TnI), creatine kinase (CK-MB) and lactate dehydrogenase (LDH). ECG showed prolongation of QRS complex, Q-T and Q-Tc interval, in addition to increased T wave voltage. There was significant increase in the relative weight of the right ventricle and the absolute and relative weights of left ventricles and the whole heart of the GM group. Moreover, GM injection resulted in a significant increase in oxidative and inflammatory markers (MDA, NO, IL-1beta, IL-6 and TNF-α) and diminished antioxidants GSH, SOD, and catalase, in the serum as well as in renal and cardiac tissues. GLP-1R agonist administration before GM injection normalized all the measured parameters only in the high dose group. Liraglutide evidently prevented upregulation of the inducible nitric oxide synthase (iNOS) gene expression in both renal and cardiac tissue of GM-treated animals.Conclusion: GM injected rats exhibited renal and cardiac structural and functional damage. The GLP-1R agonist, liraglutide protects both the kidney and the heart through antioxidant and anti-inflammatory effects. In addition, it downregulates the iNOS expression in renal and cardiac tissues, thus decreasing production of nitric oxide (NO).

ATF3 expression in cardiomyocytes and myofibroblasts following transverse aortic constriction displays distinct phenotypes.

BackgroundActivating transcription 3 (ATF3) is a member of the basic leucine zipper family of transcription factors. ATF3 is an immediate early gene expressed following various cellular stresses. ATF3 acts through binding to cyclic AMP response elements found in the promoters of key regulatory proteins that determine cell fate. In the heart, multiple cardiac stresses result in chronic ATF3 expression. Transgenic mice with ATF3 expression in cardiomyocytes clearly demonstrate that ATF3 serves a leading role in heart hypertrophy, cardiac fibrosis, cardiac dysfunction and death. In contrast, the use of ATF3 whole body knockout mice resulted non-conclusive results. The heart is composed of various cell types such as cardiomyocytes, fibroblasts, endothelial and immune cells. The question that we addressed in this study is whether ablation of ATF3 in unique cell types in the heart results in diverse cardiac phenotypes.MethodsATF3-flox mice were crossed with αMHC and Postn specific promoters directing CRE expression and thus ATF3 ablation in cardiomyocytes and myofibroblast cells. Mice were challenged with transverse aortic constriction (TAC) for eight weeks and heart function, ventricle weight, hypertrophic markers, fibrosis markers and ATF3 expression were assessed by qRT-PCR.ResultsThe results of the study show that ATF3 deletion in cardiomyocytes followed by TAC resulted in reduced heart growth and dampened fibrosis response while ATF3 ablation in myofibroblasts displayed a reduced hypertrophic gene program.ConclusionsTAC-operation results in increased ATF3 expression in both myofibroblasts and cardiomyocytes that promotes a hypertrophic program and fibrotic cardiac growth, respectively.

Perillyl alcohol suppresses monocrotaline-induced pulmonary arterial hypertension in rats via anti-remodeling, anti-oxidant, and anti-inflammatory effects

ABSTRACT Background: Pulmonary arterial hypertension (PAH) is a disastrous disease that current treatments cannot prevent its progression. The present study investigated the effects of perillyl alcohol (PA), a natural monoterpene, on the experimental PAH in male Wistar rats. Methods: Rats divided into eight groups of control, Monocrotaline (MCT), MCT+vehicle, and MCT+PA with doses of 20, 30, 40, 50, and 60 mg/kg. PAH was induced by a single injection of monocrotaline (60 mg/kg) on day 0. The animals in the groups of MCT+vehicle and MCT+PA received the vehicle or PA from day 22 to 42 once a day. On day 43, under general anesthesia, right ventricular systolic pressure (RVSP), as an index of pulmonary artery systolic pressure, and the ratio of the right ventricle to the left ventricle plus septum weight, as the right ventricular hypertrophy index (RVHI), were measured. Also, some histological and biochemical indices were assessed in the lung tissue. Results: MCT significantly (p < .001) enhanced the RVSP and RVHI compared to the control group (89.4 ± 8.2 vs 23 ± 3.3 mmHg & 0.63 ± 0.08 vs 0.26 ± 0.04 respectively). It also increased oxidative stress and inflammatory cytokines and reduced Bax/Bcl2 ratio. Treatment with PA significantly recovered RVSP and hypertrophy index and suppressed vascular cell proliferation, oxidant production, and inflammatory processes. Conclusion: PA exerted noticeable protective and curative effects against MCT-induced PAH and pulmonary vascular remodeling through inhibiting cellular proliferation, oxidative stress, and inflammation. Therefore, PA can be considered as a new therapeutic goal for the treatment of PAH.

Abstract 14613: Preclinical Animal Model of Doxorubicin-induced Left Ventricular Dysfunction: Echocardiography and Pressure-volume Analysis

Introduction: There is a need to implement a preclinical model in addition to the well established ischemic or volume-overload models that would mimic the clinical course of patients with chemotherapy-induced heart failure. Doxorubicin is an anthracycline chemotherapeutic that is widely used in oncology, although its cardiotoxicity. Hypothesis: Doxorubicin-induced left ventricular dysfunction in rats fulfills echocardiography and hemodynamic characteristics of chemotherapy-induced heart failure. Methods: We randomly assigned Ren-2 transgenic hypertensive (TGR, n = 17) and normotensive rats (HanSD, n = 22), at the age of 8 weeks to doxorubicin (2.5 mg/kg in 0.5 ml of normal saline) or placebo in 6 intraperitoneal doses within two weeks (cumulative doxorubicin dose 15 mg/kg). Two weeks later, we performed echocardiography study, pressure-volume analysis (PV), and we weighed the organs. Results: In doxorubicin groups, there was a decrease in the left ventricle weight (1,22 vs. 0,85 g in TGR), while an increase in wall stress (22036 vs. 29754 μL*mmHg/g in TGR). Echocardiography suggested heart remodeling with a decrease in relative wall thickness - RWT (1.02 vs. 0.65 mm in TGR), and together with PV analysis showed a decrease in systolic parameters - left ventricle ejection fraction - LVEF (71.41 vs. 59.96 % in TGR), end-systolic pressure-volume ratio - ESPVR (0.82 vs. 0.45 mmHg/uL in TGR) and preload recruitable stroke work - PRSW (75.71 vs. 60.98 mmHg in TGR). Ventricular-arterial coupling (VAC = Ea/Ees, a measure of cardiac efficiency) was worsened in the doxorubicin groups (1.69 vs. 2.52 in TGR). For all the above p &lt; 0.05, in HanSD, the results were similar (all p &lt; 0.05). Conclusions: Our results suggest that systolic dysfunction and decrease of cardiac efficiency in this model could be caused by heart atrophy, and such an animal model could potentially be an easily reproducible model of chemotherapy-induced heart failure in preclinical cardio-oncology studies.

Empagliflozin treatment does not affect the hypertensive response to Ang II administration to rats but decreases oxidative stress in the arterial wall, and endothelial and cardiac dysfunction

Abstract Background Selective sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown cardiovascular protection in type 2 diabetes patients with established cardiovascular disease independently of glycemic control. Angiotensin II (Ang II) and H2O2 have been shown to be strong inducers of the expression of SGLT2 and 1 in endothelial cells promoting oxidative stress and endothelial dysfunction. Purpose This study examined the cardiovascular protective effect of empagliflozin (empa) in a normoglycemic experimental model of hypertension in the rat. Methods Male Wistar rats received empa (30 mg/kg/day) provided in the diet for 5 weeks. After 1 week, rats underwent sham surgery (sham rats) or surgery with implantation of an osmotic mini-pump infusing Ang II (0.4 mg/kg/d) for 4 weeks. Systolic blood pressure (SBP) was assessed by sphygmomanometry, the cardiac function using echocardiography, the expression level of target proteins by immunofluorescence staining, and the level of oxidative stress using dihydroethidium staining. Results Angiotensin II administration increased systolic blood pressure from about 130 to 180 mmHg, which was not affected by the empa treatment. The 4-week Ang II treatment did not significantly affect the systolic cardiac function (cardiac output, left ventricle ejection fraction) but impaired the diastolic function as indicated by a reduced E' and IVRT values, and an increased E/E' value. The Ang II treatment increased significantly the heart and right ventricle weight whereas the left ventricle + septum weight was slightly but not significantly increased. No such functional and structural changes were observed in the Ang II + empa treatment group. An increased immunofluorescence eNOS signal in the endothelium, and a higher level of ROS throughout the aorta wall were observed in the Ang II-treated group, both of which were significantly reduced in the empa + Ang II-treated group. In the Ang II-treated group, the high level of oxidative stress in the aorta was significantly reduced by the AT1 receptor antagonist losartan, the NADPH oxidase inhibitor VAS-2871, the eNOS inhibitor NG-nitro-L-arginine and also to a greater extent by the selective SGLT2 inhibitor empa compared to the dual SGLT1/2 inhibitor sotagliflozin. Conclusion(s) The present findings indicate that although the empa treatment did not affect the hypertensive response of rats to Ang II, the SGLT2 inhibitor prevented the deleterious impact of Ang II on the diastolic cardiac function and remodeling, and the upregulation of eNOS expression and oxidative stress in the aorta wall. Thus, these findings highlight the protective potential of empa on the cardiovascular system in a normoglycemic hypertensive experimental model. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boehringer Ingelheim Pharma GmbH &amp; Co KG (Biberach an der Riss, Germany)

Pirfenidone and Vitamin D Ameliorate Cardiac Fibrosis Induced by Doxorubicin in Ehrlich Ascites Carcinoma Bearing Mice: Modulation of Monocyte Chemoattractant Protein-1 and Jun N-terminal Kinase-1 Pathways.

Treatment of breast cancer with doxorubicin causes numerous side effects, of which cardiac fibrosis is considered the main one. This study was designed to investigate the underlying molecular mechanisms for the potential anti-fibrotic effect of pirfenidone and vitamin D against doxorubicin-induced cardiac fibrosis. Seventy mice carrying solid Ehrlich’s ascites carcinoma (EAC) discs on the ventral side were treated with orally administered pirfenidone (500 mg/kg) and intraperitoneal injection of vitamin D (0.5 µg/kg) either individually or in combination with a doxorubicin (15 mg/kg; i.p.) single dose. All treatments commenced one week post-tumor inoculation and continued for 14 days. Compared to control EAC mice, the doxorubicin group showed a significant increase in heart and left ventricle weights, troponin T, and creatinine kinase serum levels. Furthermore, the doxorubicin group depicts a high expression of monocyte chemoattractant protein (MCP-1), nuclear factor-kappa B (NF-κB), transforming growth factor-beta 1 (TGF-β1), smad3, Jun N-terminal Kinase-1 (JNK1), and alpha-smooth muscle actin (α-SMA). Treatment with pirfenidone or vitamin D significantly decreased all of these parameters. Furthermore, the expression of smad7 was downregulated by doxorubicin and improved by pirfenidone or vitamin D. Furthermore, all treated groups showed a marked decrease in tumor weight and volume. Current data demonstrate that pirfenidone and vitamin D represent an attractive approach to ameliorate the cardiac fibrosis produced by doxorubicin through inhibiting both JNK1 signaling and MCP-1 inflammatory pathways, thus preserving heart function. Further, this combination demonstrated an anti-tumor effect to combat breast cancer.

Vitamin A deficiency indicating as low expression of LRAT may be a novel biomarker of primary hypertension

ABSTRACT Aims Vitamin A (VA) deficiency triggers many diseases and is a worldwide nutrition problem. The Retinol acyltransferase (LRAT) is an indicator of VA storage function, and the relationship between LRAT and blood pressure level and the regulation mechanism will be elucidated. Methods 160 children aged 6–12 years were included, and the serum VA and, the transcription levels of LRAT and RARs, were measured. Spontaneously hypertensive rats (SHRs) and WKY rats were treated with VA deficiency (VAD) or normal (VAN) fodder for 20 weeks. LRAT, retinoic acid, renin angiotensin system (RAS) biomarkers, and the structure and function of the heart for SHRs were measured. Results The serum retinol and serum retinol/BMI levels were lower in children in the low LRAT group (LRAT<P50) compared with the high LRAT group (LRAT≥P50)(0.82 μmol/L vs. 0.94 μmol/L, 0.04 vs. 0.05, all P < .01). Moreover, SBP, DBP, and Ang Ⅱ were lower in the low LRAT group (all P < .01). Compared with VAN-treated SHRs, LRAT, retinoic acid receptor alpha (RARα), ACE2, and Ang (1–7) protein expression levels were decreased, while ACE and AT1R expression levels were increased in VAD SHRs. Notably, heart weight (HW), left ventricle weight, the HW-to-body weight ratio and the left ventricle weight-to-body weight ratio were significantly increased in VAD SHRs compared with those in VAN SHRs (P < .01). Cardiomyocyte hypertrophy and ventricular fibrosis were significantly increased in VAD SHRs compared with those in VAN SHRs (both P < .01). Conclusions LRAT may be an important biomarker of vitamin A deficiency in target organs and may regulate BP by affecting RAS biomarkers.