Cardiac Hypertrophy In Rats Research Articles

Artesunate attenuates isoprenaline induced cardiac hypertrophy in rats via SIRT1 inhibiting NF-κB activation

Cardiac Hypertrophy is an adaptive response of the body to physiological and pathological stimuli, which increases cardiomyocyte size, thickening of cardiac muscles and progresses to heart failure. Downregulation of SIRT1 in cardiomyocytes has been linked with the pathogenesis of cardiac hypertrophy. The present study aimed to investigate the effect of Artesunate against isoprenaline induced cardiac hypertrophy in rats via SIRT1 inhibiting NF-κB activation. Experimental cardiac hypertrophy was induced in rats by subcutaneous administration of isoprenaline (5 mg/kg) for 14 days. Artesunate was administered simultaneously for 14 days at a dose of 25 mg/kg and 50 mg/kg. Artesunate administration showed significant dose dependent attenuation in mean arterial pressure, electrocardiogram, hypertrophy index and left ventricular wall thickness compared to the disease control group. It also alleviated cardiac injury biomarkers and oxidative stress. Histological observation showed amelioration of tissue injury in the artesunate treated groups compared to the disease control group. Further, artesunate treatment increased SIRT1 expression and decreased NF-kB expression in the heart. The results of the study show the cardioprotective effect of artesunate via SIRT1 inhibiting NF-κB activation in cardiomyocytes.

Sildenafil Effect on Atrial Natriuretic Peptide Level in Pulmonary Hypertensive Rats.

Pulmonary Hypertension (PH) leads to changes in pulmonary vascular architecture, hypertrophy of the right ventricle, and heart failure. Sildenafil is a drug that can modulate PH by inducing smooth muscle relaxation and vasodilation. To investigate the ability of sildenafil to alleviate the monocritaline (MCT)-induced PH in rats and to estimate the role and its effect on the atrial natriuretic peptide (ANP) levels. 28 adult male rats were divided randomly into four groups: Group A (control group; n=7). Group B (MCT-treated group; n=7) was given a single dose of MCT 60 mg/kg subcutaneously. Group C (The reversal group; n=7) received a single dose of MCT 60 mg/kg subcutaneously for three weeks and then sildenafil at 50 mg/kg/day, given daily for another three weeks. Group D (The prevention group; n=7) simultaneously received a single dose of MCT 60 mg/kg subcutaneously and sildenafil daily at 50 mg/kg for three weeks. The animals in the prevention group showed a significant decrease in ANP levels compared to the reversal and MCT-treated groups. This decrease was associated with a significant reduction in the Fulton index ratio in the prevention group compared to the reversal group. The nitric oxide levels were also significantly higher in the reversal group than in the control group. Preventive sildenafil treatment was associated with a significant decrease in ANP levels and reduced MCT-induced cardiac hypertrophy in rats.

A pseudo-targeted metabolomics for discovery of potential biomarkers of cardiac hypertrophy in rats

Cardiac hypertrophy (CH) is one of the stages in the occurrence and development of severe cardiovascular diseases, and exploring its biomarkers is beneficial for delaying the progression of severe cardiovascular diseases. In this research, we established a comprehensive and highly efficient pseudotargeted metabolomics method, which demonstrated a superior capacity to identify differential metabolites when compared to traditionaluntargeted metabolomics. The intra/inter-day precision and reproducibility results proved the method is reliable and precise. The established method was then applied to seek the potential differentiated metabolic biomarkers of cardiac hypertrophy (CH) rats, and oxylipins, phosphorylcholine (PC), lysophosphatidylcholine (LysoPC), lysophosphatidylethanolamine (LysoPE), Krebs cycle intermediates, carnitines, amino acids, and bile acids were disclosed to be the possible differentiate components. Their metabolic pathway analysis revealed that the potential metabolic alterations in CH rats were mainly associated with phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, arachidonic acid metabolism, citrate cycle, glyoxylate and dicarboxylate metabolism, and tyrosine metabolism. In sum, this research provided a comprehensiveand reliable LC-MS/MS MRM platform for pseudo-targeted metabolomics investigation of disease condition, and some interesting potential biomarkers were disclosed for CH, which merit further exploration in the future.

The molecular mechanism of MiR-26a-5p regulates autophagy and activates NLRP3 inflammasome to mediate cardiomyocyte hypertrophy

ObjectiveMany studies have found that miR-26a-5p plays an essential role in the progression of pathological cardiac hypertrophy, however, there is still no evidence on whether miR-26a-5p is related to the activation of autophagy and NLRP3 inflammasome. And the mechanism of miR-26a-5p and NLRP3 inflammasome aggravating pathological cardiac hypertrophy remain unclear.MethodsCardiomyocytes were treated with 200µM PE to induce cardiac hypertrophy and intervened with 10mM NLRP3 inhibitor INF39. In addition, we also used the MiR-26a-5p mimic and inhibitor to transfect PE-induced cardiac hypertrophy. RT-qPCR and western blotting were used to detect the expressions of miR-26a-5p, NLRP3, ASC and Caspase-1 in each group, and we used α-SMA immunofluorescence to detect the change of cardiomyocyte area. The expression levels of autophagy proteins LC3, beclin-1 and p62 were detected by western blotting. Finally, we induced the SD rat cardiac hypertrophy model through aortic constriction (TAC) surgery. In the experimental group, rats were intervened with MiR-26a-5p mimic, MiR-26a-5p inhibitor, autophagy inhibitor 3-MA, and autophagy activator Rapamycin.ResultsIn cell experiments, we observed that the expression of miR-26a-5p was associated with cardiomyocyte hypertrophy and increased surface area. Furthermore, miR-26a-5p facilitated autophagy and activated the NLRP3 inflammasome pathway, which caused changes in the expression of genes and proteins including LC3, beclin-1, p62, ACS, NLRP3, and Caspase-1. We discovered similar outcomes in the TAC rat model, where miR-26a-5p expression corresponded with cardiomyocyte enlargement and fibrosis in the cardiac interstitial and perivascular regions. In conclusion, miR-26a-5p has the potential to regulate autophagy and activate the NLRP3 inflammasome, contributing to the development of cardiomyocyte hypertrophy.ConclusionOur study found a relationship between the expression of miR-26a-5p and cardiomyocyte hypertrophy. The mechanism behind this relationship appears to involve the activation of the NLRP3 inflammasome pathway, which is caused by miR-26a-5p promoting autophagy. Targeting the expression of miR-26a-5p, as well as inhibiting the activation of autophagy and the NLRP3 inflammasome pathway, could offer additional treatments for pathological cardiac hypertrophy.

Linagliptin and secoisolariciresinol diglucoside attenuate hyperlipidemia and cardiac hypertrophy induced by a high-methionine diet in rats via suppression of hyperhomocysteinemia-induced endoplasmic reticulum stress.

Background: Cardiac hypertrophy (CH) is one of the contributing causes of morbidity and mortality. Hyperhomocysteinemia (HHcy) is one of the diseases which may predispose hyperlipidemia and CH. Linagliptin (Lina) and secoisolariciresinol diglucoside (SDG) are known to alleviate a variety of illnesses by reducing oxidative stress and inflammation. Aim: This study aimed to study the effect of HHcy on cardiac tissues, with a special focus on endoplasmic reticulum (ER) stress as a mainstay pathophysiological pathway. In addition, our study examined the protective effect of Lina, SDG, and their combination against HHcy-induced hyperlipidemia and CH in rats. Methods: Seventy-five male Sprague-Dawley rats were randomly divided into five groups, and for 60days, the following regimen was administered: Group I: rats received distilled water; Group II: rats received methionine (MET) (2g/kg/day, p.o.); groups III and IV: rats received Lina (3mg/kg/day, p.o.) and SDG (20mg/kg/day, p.o.), respectively, followed by MET (2g/kg/day, p.o.); Group V: rats received Lina and SDG, followed by MET (2g/kg/day, p.o.). Results: Pretreatment with Lina, SDG, and their combination showed a significant decrease in serum levels of HHcy and an improved lipid profile compared to the MET group. Moreover, both drugs improved cardiac injury, as evidenced by the substantial improvement in ECG parameters, morphological features of the cardiac muscle, and reduced serum levels of cardiac markers. Additionally, Lina and SDG significantly attenuated cardiac oxidative stress, inflammation, and apoptosis. Furthermore, Lina, SDG, and their combination remarkably downregulated the enhanced expression of endoplasmic reticulum (ER) stress markers, GRP78, PERK, ATF-4, CHOP, NF-κB, and SREBP1c compared to the MET-group. Conclusion: Lina and SDG showed cardioprotective effects against HHcy-induced heart hypertrophy and hyperlipidemia in rats.

Vitamin D Attenuates Cardiac Hypertrophy in Rats through mRNA Regulation of Interleukin-6 and Its Receptor

Abstract Context: Interleukin-6 (IL-6), a pro-inflammatory cytokine, plays an important role in the pathogenesis of myocardial hypertrophy. By integrating its membrane receptor complex (gp80), IL-6 activates the signal guidance components (gp130) and activates the hypertrophic signaling pathways. There is some evidence that 1,25 dihydroxyvitamin D exerts antihypertrophic effects, but the cellular and molecular mechanisms are not fully understood. The aim of this study was to evaluate the effect of calcitriol on the level of IL-6 and its receptor components in hypertrophied rat heart. Subjects and Methods: Male rats were divided into control, hypertrophy, Vitamin D + hypertrophy, and propylene glycol + hypertrophy groups. The groups receiving Vitamin D and propylene glycol were treated 2 weeks before induction of hypertrophy and 2 weeks after hypertrophy. Myocardial hypertrophy was induced by abdominal aortic stenosis. Mean arterial blood pressure was measured by cannulation of the left carotid artery, and expression of genes was determined by reverse transcription-polymerase chain reaction. Results: Blood pressure and heart-to-body weight ratio increased in hypertrophic groups compared to the control group (P < 0.01), but Vitamin D administration decreased these parameters (P < 0.05). Abdominal aortic stenosis increased IL-6 expression levels (P < 0.001) and Vitamin-D decreased IL-6 mRNA levels (P < 0.01). The expression of gp80 in the hypertrophic group increased compared to the control group (P < 0.05), but Vitamin D did not affect the expression of receptor subunits genes. Conclusions: The data from this study suggest a possible mechanism for the antihypertrophic effects of Vitamin D through the regulation of inflammatory responses during hypertrophy. Thus, Vitamin D can reduce IL-6 expression levels, thereby reducing hypertrophy.

Exploring the Interactive Role of Parathyroid Hormone and Sodium Intake in Inducing Cardiac Hypertrophy in Rats: A Novel Study.

Background and objectives Previous research has suggested that hyperparathyroidism and excessive salt intake may contribute to the development of cardiac hypertrophy. This study aimed to investigate the relationship and underlying mechanisms between parathyroid hormone (PTH) and salt intake in the development of left ventricular hypertrophy (LVH). Additionally, the study sought to determine whether captopril intervention could reduce the impact of sustained PTH stimulation and excessive salt intake on LVH. Methodology We employed 40 eight-week-old male Sprague-Dawley rats, which were randomly assigned to eight groups: a sham group, a PTH group, a low-salt group (0.6% NaCl), a high-salt group (8% NaCl), a PTH + low-salt group, a PTH + high-salt group, a PTH + low salt + captopril group, and a PTH + high salt + captopril group. The rats were continuously infused with recombinant PTH (1-34) (2 pmol/kg per hour) via an osmotic pump for two weeks and were administered varying concentrations of saline for gavage over two weeks, according to their group. We monitored changes in blood pressure, measured heart weight, left ventricular wall thickness, and myocardial histological morphology, and assessed the relative expression of type III collagen. Results The PTH + high-salt group displayed a significant increase in blood pressure, heart weight, and left ventricular posterior wall thickness (P＜0.05), in addition to myocardial cell hypertrophy and increased Col III expression (P＜0.05), compared to other groups. Captopril intervention significantly reduced blood pressure (P＜0.05), ameliorated myocardial tissue morphology changes, and significantly decreased Col III expression (P＜0.05) but did not entirely reverse the increase in heart weight and left ventricular posterior wall thickness (P＞0.05). Conclusions Our findings suggest that the co-intervention of PTH and high salt can lead to an increase in blood pressure, heart weight, myocardial cell hypertrophy, LVH, and myocardial fibrosis levels in Sprague-Dawley rats. Captopril intervention can lower blood pressure and alleviate pathological myocardial tissue changes and myocardial fibrosis but cannot completely reverse LVH.

The Role of Extracellular Signal-Regulated Kinase Pathways in Different Models of Cardiac Hypertrophy in Rats.

Cardiac hypertrophy develops following different triggers of pressure or volume overload. In several previous studies, different hypertrophy types were demonstrated following alterations in extracellular signal-regulated kinase (ERK) pathway activation. In the current study, we studied two types of cardiac hypertrophy models in rats: eccentric and concentric hypertrophy. For the eccentric hypertrophy model, iron deficiency anemia caused by a low-iron diet was implemented, while surgical aortic constriction was used to induce aortic stenosis (AS) and concentric cardiac hypertrophy. The hearts were evaluated using echocardiography, histological sections, and scanning electron microscopy. The expression of ERK1/2 was analyzed using Western blot. During the study period, anemic rats developed eccentric hypertrophy characterized by an enlarged left ventricle (LV) cavity cross-sectional area (CSA) (59.9 ± 5.1 mm2 vs. 47 ± 8.1 mm2, p = 0.002), thinner septum (2.1 ± 0.3 mm vs. 2.5 ± 0.2 mm, p < 0.05), and reduced left ventricular ejection fraction (LVEF) (52.6% + 4.7 vs. 60.3% + 2.8, p < 0.05). Rats with AS developed concentric hypertrophy with a thicker septum (2.8 ± 0.6 vs. 2.4 ± 0.1 p < 0.05), increased LV muscle cross-sectional area (79.5 ± 9.33 mm2 vs. 57.9 ± 5.0 mm2, p < 0.001), and increased LVEF (70.3% + 2.8 vs. 60.0% + 2.1, p < 0.05). ERK1/2 expression decreased in the anemic rats and increased in the rats with AS. Nevertheless, the p-ERK and the p-MEK did not change significantly in all the examined models. We concluded that ERK1/2 expression was altered by the type of hypertrophy and the change in LVEF.

Astragaloside IV attenuates cardiac hypertrophy in rats born from mothers with intrauterine hypoxia through the PKCβII/Egr‑1 pathway.

Astragaloside IV (AS-IV) is a naturally occurring agent that confers several wide-ranging reported pharmacological effects, such as cardioprotective, antioxidative and pro-angiogenic activities. Although it was previously reported that AS-IV could attenuate neonatal rat myocardial ischemia-reperfusion injury, the possible effects of AS-IV on the development of cardiac hypertrophy associated with intrauterine hypoxia (IUH) remain unclear. The present study established a model of IHU by placing the pregnant rats in a plexiglass chamber with an oxygen supply of 10% before neonatal rat delivery. To investigate the in vivo effect of AS-IV on cardiac hypertrophy, neonatal rats with hypertension were randomly grouped to receive AS-IV (20 mg/kg), AS-IV (40 mg/kg), AS-IV (80 mg/kg) or vehicle for 12 weeks, followed by left ventricular (LV) hemodynamics and heart tissue histological analysis. Rats born from mothers with IHU displayed pathological features of cardiac hypertrophy. However, AS-IV 40 and 80 mg/kg significantly decreased the heart/body weight (BW), LV mass (LVM)/BW, heart mass/tibia length (TL) and LVM/TL ratios. H&E staining showed that 40 and 80 mg/kg AS-IV prevented the morphometric changes induced by IHU. According to data from LV hemodynamics measurements, AS-IV 80 mg/kg reversed the increased systolic blood pressure, diastolic blood pressure, LV systolic pressure, LV end-diastolic pressure, dP/dt maximum and heart rate induced by IHU. Mechanistically, ERK1/2 activation and early growth response 1 (Egr-1) protein expression were both upregulated by IHU induction, which was reversed by AS-IV treatment. In conclusion, these data suggested that AS-IV could attenuate cardiac hypertrophy in neonatal rats born from mothers with IHU through the protein kinase C β type isoform 2/Egr-1 pathway, but the underlying mechanism requires further investigation.

Experimental research on the evaluation of left ventricular systolic function by layered speckle tracking before and after berberine treatment in a cardiac hypertrophy rat model.

To evaluate the effect of berberine (BBR) intervention on left ventricular hypertrophy and systolic function in rats by ultrasound layered strain imaging and cardiac hypertrophy model. Eighty healthy male Sprague-Dawley (SD) rats were randomly divided into four groups: group A (normal saline control group), group B [isoproterenol (ISO) induced model group], group C (BBR hydrochloride 5 mg/kg + ISO group) and group D (BBR hydrochloride 10 mg/kg + ISO group). Echocardiography was performed on days 1, 7 and 14, respectively. The myocardial tissue was taken for pathological examination. The key proteins of Rho/ROCK signaling pathway were quantified by immunohistochemical staining. On day 7, compared with group A, peripheral strain values of the subendocardium and middle myocardium of rats in groups B, C and D were significantly decreased. The absolute value of circumferential strain (CS) in subendocardium and middle myocardium in group B was significantly lower than that in groups C and D (-24.21 vs. -26.68 vs. -27.69; -14.90 vs. -16.48 vs. -17.69). Pathological results showed that compared with the myocardial cells in control group A, the myocardial cells in group B had significantly increased cross-sectional area, and obvious myocardial interstitial fibrosis. Compared with group B, BBR intervention reduced the deposition of fibrosis in groups C and D, group D was more obvious. Immunohistochemical results showed that compared with group A, the protein expression levels of ROCK, RhoA and Bax in groups B, C and D were significantly increased, while the protein expression levels of Bcl-2 were significantly decreased. Ultrasound layered strain imaging could evaluate the early left ventricular systolic function in isoprenaline-induced hypertrophy rat model. BBR might inhibit oxidative stress through the Rho/ROCK signaling pathway and slow down the progression of myocardial fibrosis after the formation of cardiac hypertrophy. This provides reference and direction for clinical decision-making and further research.

PS-B04-7: CHRYSIN AMELIORATES ISOPROTERENOL-INDUCED CARDIAC HYPERTROPHY IN RATS VIA MODULATION OF SIGNALING PATHWAYS

Objective: Chrysin, a flavonoid, obtained from honey has shown to possess various pharmacological activities such as anti-oxidant, anti-apoptotic, anti-fibrotic and anti-inflammatory. Isoproterenol (ISO) induced cardiac hypertrophy involve development of oxidative stress, inflammation and fibrosis in the rats. On this basis, the present study was designed to investigate the effect of chrysin in ISO-induced cardiac hypertrophy in rats. Design and method: Male albino Wistar rats were divided into seven groups (n = 6): Normal, ISO-control and chrysin treatment groups (15, 30 and 60 mg/kg; p.o.), chrysin per se (60 mg/kg; p.o.) and combination group (chrysin 60 mg/kg; p.o. + losartan 10 mg/kg; p.o.). Chrysin was administered for the period of 28 days. Hypertrophy in all groups were induced by administration of ISO at the dose of 3 mg/kg; s.c. other than normal and per se groups. On 29th day, rats were anaesthetised, hemodynamic parameters were measured, blood was withdrawn and heart was excised. Heart was stored for the estimation of biochemical, histopathological, ultrastructural, and molecular studies. Results: Chrysin treatment for 28 days significantly improved heart to body weight ratio, normalized hemodynamic parameters, strengthen antioxidant parameters, prevented release of cardiac injury markers and attenuated pathological changes. In addition, it also reduced inflammation (decreased TNF-α, IL-6, pNF-κB/NF-κB ratio), apoptosis (increased Bcl-2 and decreased Bax, caspase-3 and PARP) and fibrosis (decreased TGF-β;/Smad) in ISO-induced hypertrophic rats. Furthermore, it also regulated the expression of various signaling pathways (MAPK, Nrf2/HO-1). All these changes were comparable to the losartan treatment group. Conclusion: Thus, chrysin pre-treatment prevented oxidative stress, inflammation, apoptosis and fibrosis in rats via alteration of various pathways. Hence, chrysin could be further studied for treatment of cardiac hypertrophy.

L-carvone attenuates myocardial injury and dyslipidemia in rats with isoproterenolinduced cardiac hypertrophy

Objective: To explore the therapeutic efficacy of L-carvone from Mentha spicataL. leaf extracts against isoproterenol-induced cardiac hypertrophy in rats. Methods: Isoproterenol (5 mg/kg) was injected intraperitoneally into rats for one month to induce cardiac hypertrophy. L-carvone (25 and 100 mg/kg) was administered orally to treat cardiac hypertrophy. The cardioprotective activity of L-carvone was evaluated by electrocardiogram, histopathological analysis as well as determination of biochemical parameters and enzymatic markers. Results: L-carvone from Mentha spicata L. at 25 and 100 mg/kg ameliorated isoproterenol-induced cardiac hypertrophy, as evidenced by reduced QRS interval on electrocardiogram, and decreased heart weight and heart index. In addition, both doses of L-carvone markedly lowered the levels of glucose, total protein, low-density lipoprotein cholesterol, aspartate transaminase, alanine transaminase, lactate dehydrogenase, creatine kinase MB, troponin-I, N-terminal pro-B type natriuretic peptide and triglycerides while increasing high-density lipoprotein cholesterol and lipase level (P&lt;0.05). Moreover, L-carvone alleviated contraction band necrosis, and reorganized the myofibrils with normal striations and myocytes as well as normal nuclei in cardiac histoarchitecture of rats with isoproterenol-induced cardiac hypertrophy. Conclusions: L-carvone from Mentha spicata L. leaf extract can restore abnormal cardiac function and may be further explored as a therapeutic agent against the deleterious effects of cardiac hypertrophy after further evaluation.

Aurintricarboxylic acid protects isoproterenol induced left ventricular hypertrophy by modulating TWEAK signaling

BackgroundCardiac hypertrophy is regarded as a compensation mechanism to overcome the increased workload. Aurintricarboxylic acid (ATA) is a derivative of quinomethanes and a selective inhibitor of TWEAK/Fn14 pathway. In this study, we investigated the effect of ATA on isoproterenol (ISO)-induced pathological cardiac hypertrophy. MethodsCardiac hypertrophy in H9C2 cells was induced using ISO 20 μM dissolved in PBS. H9C2 cells were treated with ATA (5 µM, 10 µM, 20 µM) followed by ISO stimulation for 24 h. Male SD rats were injected ISO (5 mg/kg/day, s.c) for 21 days and followed by treatment with ATA (10 mg/kg, i.p.) for 14 days. Cardiac functions were assessed. After sacrifice, hearts were subjected to histopathological and western blot analysis. ResultsIn in-vitro results, upon ATA treatment, ICC results showed significant decrease in TWEAK and ANP expression. In in-vivo results, echocardiography showed significant restoration of cardiac function in ATA treated rats. Histopathological analysis showed a significant decrease in left ventricular wall thickness, cardiomyocytes width and reduced fibrosis in ATA treated rats. Western blotting showed decreased expression of the cardiac hypertrophy maker ANP, inflammatory markers including TWEAK and apoptotic markers after ATA treatment. ConclusionThese findings suggested that the TWEAK/Fn14 pathway could be a potential target for therapeutic exploration in ISO induced cardiac hypertrophy. ATA, as an inhibitor of this pathway, exerted significant cardioprotective effect against ISO-induced cardiac hypertrophy in rats.

Ameliorative Role of Fluconazole Against Abdominal Aortic Constriction-Induced Cardiac Hypertrophy in Rats.

Cytochrome P450 1B1 (CYP1B1) is known to be involved in the pathogenesis of several cardiovascular diseases, including cardiac hypertrophy and heart failure, through the formation of cardiotoxic metabolites named as mid-chain hydroxyeicosatetraenoic acids (HETEs). Recently, we have demonstrated that fluconazole decreases the level of mid-chain HETEs in human liver microsomes, inhibits human recombinant CYP1B1 activity, and protects against angiotensin II-induced cellular hypertrophy in H9c2 cells. Therefore, the overall purpose of this study was to elucidate the potential cardioprotective effect of fluconazole against cardiac hypertrophy induced by abdominal aortic constriction (AAC) in rats. Male Sprague-Dawley rats were randomly assigned into 4 groups such as sham control rats, fluconazole-treated (20 mg/kg daily for 4 weeks, intraperitoneal) sham rats, AAC rats, and fluconazole-treated (20 mg/kg) AAC rats. Baseline and 5 weeks post-AAC echocardiography were performed. Gene and protein expressions were measured using real-time PCR and Western blot analysis, respectively. The level of mid-chain HETEs was determined using liquid chromatography-mass spectrometry. Echocardiography results showed that fluconazole significantly prevented AAC-induced left ventricular hypertrophy because it ameliorated the AAC-mediated increase in left ventricular mass and wall measurements. In addition, fluconazole significantly prevented the AAC-mediated increase of hypertrophic markers. The antihypertrophic effect of fluconazole was associated with a significant inhibition of CYP1B1, CYP2C23, and 12-LOX and a reduction in the formation rate of mid-chain HETEs. This study demonstrates that fluconazole protects against left ventricular hypertrophy, and it highlights the potential repurposing of fluconazole as a mid-chain HETEs forming enzymes' inhibitor for the protection against cardiac hypertrophy.

Hydrogen Attenuates Thyroid Hormone-Induced Cardiac Hypertrophy in Rats by regulating angiotensin II type 1 receptor and NADPH oxidase 2 mediated oxidative stress

Cardiac hypertrophy occurs as a result of high levels of thyroid hormone, which may contribute to heart failure and is closely related to oxidative stress. Hydrogen is a good antioxidant. In this study, we found that intragastric levothyroxine administration for two weeks caused obvious cardiac hypertrophy without reduced systolic function. Additionally, hydrogen inhalation ameliorated the levothyroxine-induced metabolic increase and cardiac hypertrophy in rats. Serum brain natriuretic peptide expression was also attenuated by hydrogen treatment. However, hydrogen had no significant effect on levothyroxine -induced serum troponin I and serum thyroid hormone changes.Hydrogen treatment also reduced the levothyroxine-induced increase in cardiac malondialdehyde, 8-hydroxy-2-deoxyguanosine and serum hydrogen peroxide levels and upregulated superoxide dismutase and glutathione peroxidase activity. Additionally, western blotting results showed that hydrogen inhalation inhibited the expression of cardiac nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), angiotensin II type 1 receptor, sarcoplasmic reticulum Ca2+-ATPase (SERCA2), phospho-phospholamban and α-myosin heavy chain proteins. In conclusion, the present study revealed a protective effect of hydrogen on levothyroxine -induced cardiac hypertrophy by regulating angiotensin II type 1 receptors and NOX2-mediated oxidative stress in rats.

Metabolomics based mechanistic insights to vasorelaxant and cardioprotective effect of ethanolic extract of Citrullus lanatus (Thunb.) Matsum. & Nakai. seeds in isoproterenol induced myocardial infraction

BackgroundCardiovascular diseases (CVDs) are a significant cause of morbidity and death in the current world, posing a challenge to both developing and industrialized nation's health systems. Citrullus lanatus (Thunb.) Matsum. & Nakai. seeds have long been utilized to supplement and enhance health and treat cardiovascular illnesses. However, its treatments for CVDs are still unknown. More research is required to fully comprehend the impact of C. lanatus seeds on vasorelaxation and myocardial infractions. PurposeTherefore, an integrated metabolomics profiling technique was used to investigate possible pathways of C. lanatus in isoproterenol (ISO)-induced myocardial infarction (MI). Isoproterenol causes long-term cardiac hypertrophy by causing cardiomyocyte compensatory loss, eventually leading to heart failure. MethodsIn vitro models of vasoconstriction, atrium, and in vivo models of invasive blood pressure measurement and isoproterenol (ISO) induced cardiac hypertrophy in rats were used to understand underlying mechanistic by LC-MS/MS based dynamic metabolomics analysis of the serum and heart samples to be investigated the effect of ethanolic extract of C. lanatus (Cl.EtOH). ResultsCl.EtOH exhibited vasorelaxant, negative chronotropic, and inotropic effects in in-vitro models whereas, a potent hypotensive effect was observed in normotensive rats. The Cl.EtOH protected the animals from ISO-induced myocardial infarction (MI) with therapeutic interventions in left ventricular thickness, cardiomyocyte hypertrophy, mRNA gene expression, biochemical assays, and metabolomic profiling of serum and heart tissues. ConclusionsFor the first time, our study confirmed that C. lanatus seeds (Cl.EtOH) possess significant antihypertensive and prevent ISO-induced myocardial infarction. These findings comprehensively demonstrated mechanistic insights of Cl.EtOH in vasorelaxation and myocardial infarction. The current study provides evidence for further mechanistic studies and the development of C. lanatus seeds as a potential therapeutic intervention for patients with cardiovascular disorders.

Alterations in gut microbiota and metabolites associated with altitude-induced cardiac hypertrophy in rats during hypobaric hypoxia challenge.

The gut microbiota is involved in host responses to high altitude. However, the dynamics of intestinal microecology and their association with altitude-related illness are poorly understood. Here, we used a rat model of hypobaric hypoxia challenge to mimic plateau exposure and monitored the gut microbiome, short-chain fatty acids (SCFAs), and bile acids (BAs) over 28 d. We identified weight loss, polycythemia, and pathological cardiac hypertrophy in hypoxic rats, accompanied by a large compositional shift in the gut microbiota, which is mainly driven by the bacterial families of Prevotellaceae, Porphyromonadaceae, and Streptococcaceae. The aberrant gut microbiota was characterized by increased abundance of the Parabacteroides, Alistipes, and Lactococcus genera and a larger Bacteroides to Prevotella ratio. Trans-omics analyses showed that the gut microbiome was significantly correlated with the metabolic abnormalities of SCFAs and BAs in feces, suggesting an interaction network remodeling of the microbiome-metabolome after the hypobaric hypoxia challenge. Interestingly, the transplantation of fecal microbiota significantly increased the diversity of the gut microbiota, partially inhibited the increased abundance of the Bacteroides and Alistipes genera, restored the decrease of plasma propionate, and moderately ameliorated cardiac hypertrophy in hypoxic rats. Our results provide an insight into the longitudinal changes in intestinal microecology during the hypobaric hypoxia challenge. Abnormalities in the gut microbiota and microbial metabolites contribute to the development of high-altitude heart disease in rats.

Up-regulation of IRF3 is required for docosahexaenoic acid suppressing ferroptosis of cardiac microvascular endothelial cells in cardiac hypertrophy rat

The molecular characteristics of ferroptosis in cardiac hypertrophy have been rarely studied. Especially, there have been no studies to investigate the regulatory mechanisms of docosahexaenoic acid (DHA) on ferroptosis in cardiac hypertrophy. This study was designed to determine the role of ferroptosis in microvascular injury, and investigate the contribution of DHA in suppressing ferroptosis and preventing pressure overload-mediated endothelial damage. Our results indicated that the expression of interferon regulating factor 3 (IRF3) was primarily inhibited by pressure overload and consequently caused endothelial ferroptosis. Nevertheless, administration of DHA increased IRF3 expression and provided a pro-survival advantage for the endothelial system in the context of pressure overload. Experimental studies clearly showed that inhibition of IRF3 down-regulated SLC7A11 expression, and the latter leaded to the increase in the activities of arachidonate 12-lipoxygenase, which obligated cardiac microvascular endothelial cells to undergo ferroptosis via augmenting lipid peroxides. Interestingly, DHA supplementation suppressed endothelial ferroptosis via up-regulation of IRF3. Taken together, our studies identified the IRF3-SLC7A11-arachidonate 12-lipoxygenase axis as a new pathway responsible for pressure overload-mediated microvascular damage via initiating endothelial ferroptosis. In contrast, DHA treatment up-regulated the expression of IRF3 and thus reduced cellular ferroptosis, conferring a protective advantage to the endothelial system in pressure overload. These findings revealed that targeting IRF3 might be a useful therapeutic strategy for cardioprotection in cardiac hypertrophy and heart failure.

Fisetin Attenuates Doxorubicin-Induced Cardiomyopathy In Vivo and In Vitro by Inhibiting Ferroptosis Through SIRT1/Nrf2 Signaling Pathway Activation

Doxorubicin (DOX) is an anthracycline antibiotic that is used extensively for the management of carcinoma; however, its clinical application is limited due to its serious cardiotoxic side effects. Ferroptosis represents iron-dependent and reactive oxygen species (ROS)-related cell death and has been proven to contribute to the progression of DOX-induced cardiomyopathy. Fisetin is a natural flavonoid that is abundantly present in fruits and vegetables. It has been reported to exert cardioprotective effects against DOX-induced cardiotoxicity in experimental rats. However, the underlying mechanisms remain unknown. The present study investigated the cardioprotective role of fisetin and the underlying molecular mechanism through experiments in the DOX-induced cardiomyopathy rat and H9c2 cell models. The results revealed that fisetin treatment could markedly abate DOX-induced cardiotoxicity by alleviating cardiac dysfunction, ameliorating myocardial fibrosis, mitigating cardiac hypertrophy in rats, and attenuating ferroptosis of cardiomyocytes by reversing the decline in the GPX4 level. Mechanistically, fisetin exerted its antioxidant effect by reducing the MDA and lipid ROS levels and increasing the glutathione (GSH) level. Moreover, fisetin exerted its protective effect by increasing the SIRT1 expression and the Nrf2 mRNA and protein levels and its nuclear translocation, which resulted in the activation of its downstream genes such as HO-1 and FTH1. Selective inhibition of SIRT1 attenuated the protective effects of fisetin in the H9c2 cells, which in turn decreased the GSH and GPX4 levels, as well as Nrf2, HO-1, and FTH1 expressions. In conclusion, fisetin exerts its therapeutic effects against DOX-induced cardiomyopathy by inhibiting ferroptosis via SIRT1/Nrf2 signaling pathway activation.

Gut Microbiome-Targeted Modulations Regulate Metabolic Profiles and Alleviate Altitude-Related Cardiac Hypertrophy in Rats.

ABSTRACTIt is well known that humans physiologically or pathologically respond to high altitude, with these responses accompanied by alterations in the gut microbiome. To investigate whether gut microbiota modulation can alleviate high-altitude-related diseases, we administered probiotics, prebiotics, and synbiotics in rat model with altitude-related cardiac impairment after hypobaric hypoxia challenge and observed that all three treatments alleviated cardiac hypertrophy as measured by heart weight-to-body weight ratio and gene expression levels of biomarkers in heart tissue. The disruption of gut microbiota induced by hypobaric hypoxia was also ameliorated, especially for microbes of Ruminococcaceae and Lachnospiraceae families. Metabolome revealed that hypobaric hypoxia significantly altered the plasma short-chain fatty acids (SCFAs), bile acids (BAs), amino acids, neurotransmitters, and free fatty acids, but not the overall fecal SCFAs and BAs. The treatments were able to restore homeostasis of plasma amino acids and neurotransmitters to a certain degree, but not for the other measured metabolites. This study paves the way to further investigate the underlying mechanisms of gut microbiome in high-altitude related diseases and opens opportunity to target gut microbiome for therapeutic purpose.IMPORTANCE Evidence suggests that gut microbiome changes upon hypobaric hypoxia exposure; however, it remains elusive whether this microbiome change is a merely derivational reflection of host physiological alteration, or it synergizes to exacerbate high-altitude diseases. We intervened gut microbiome in the rat model of prolonged hypobaric hypoxia challenge and found that the intervention could alleviate the symptoms of pathological cardiac hypertrophy, gut microbial dysbiosis, and metabolic disruptions of certain metabolites in gut and plasma induced by hypobaric hypoxia. Our study suggests that gut microbiome may be a causative factor for high-altitude-related pathogenesis and a target for therapeutic intervention.