Myocardial Hypertrophy In Rats Research Articles

Changes in glutamic oxaloacetic transaminase 2 during rat physiological and pathological cardiomyocyte hypertrophy

BackgroundPhysiological and pathological cardiomyocyte hypertrophy are important pathophysiological processes of adult congenital heart disease-associated ventricular hypertrophy. Glutamic oxaloacetic transaminase (GOT) is a vital marker of myocardial injury. This study aimed to investigate the changes in GOT levels during physiological and pathological cardiomyocyte hypertrophy in rats.MethodsRNA-seq analysis and colorimetric methods were used to evaluate the changes in GOT mRNA and activity, respectively. GOT2 protein expression was detected by western blotting and immunofluorescence. Hematoxylin-eosin and wheat germ agglutinin methods were used to observe changes in rat cardiomyocyte morphology.ResultsIn juvenile rat hearts, GOT mRNA expression and activity, and GOT2 protein level increased with age-related physiological cardiomyocyte hypertrophy; however, GOT2 protein level was reduced in hypoxia-induced pathological cardiomyocyte hypertrophy.ConclusionsGOT2 may regulate physiological and pathological myocardial hypertrophy in rats. We speculated that the low GOT2 level contributed to the rapid occurrence of pathological cardiomyocyte hypertrophy, causing strong plasticity of right ventricular cardiomyocytes in the early postnatal period and heart failure in adulthood.

PS-B02-10: MTOR INHIBITOR IMPROVES TESTOSTERONE-INDUCED MYOCARDIAL HYPERTROPHY IN HYPERTENSIVE RATS

Compelling evidence have described the incidence of hypertension and left ventricular hypertrophy in postmenopausal women is significantly increased worldwide. Our team previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mTOR signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. For that, ovariectomized spontaneously hypertensive rats aged 12 weeks were used to study the effects of testosterone T 2.85 mg/kg/weekly im on blood pressure and myocardial tissue. On the basis of antihypertensive therapy chlorthalidone 8 mg/kg/day ig, the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin 0.8 mg/kg/day Vs 1.5 mg/kg/day Vs 2 mg/kg/day ip in OVX+ estrogens E 9.6 mg/Kg/day, ig+T group was further evaluated. After T intervention, the OVX female rats exhibited significant increments in the heart weight / tibial length, cross-sectional area of cardiomyocytes and the mRNA expressions of atrial natriuretic peptide, myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and issue inhibitor of metalloproteinase 1. Mammalian rapamycin receptor mTOR, ribosomal protein S6 kinase S6K1, 4E-bindiong protein 1 4EBP1 and eukaryotic translation initiation factor 4E in myocardial tissue of OVX+E+T group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of T-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/ S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive women with high T levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate T-induced cardiomyocyte hypertrophy.

Myocardial effects of a low-protein diet in experimental kidney dysfunction

THE AIM: to evaluate the effect of low protein diet supplemented with ketosteril on morphological and epigenomic changes in the myocardium of Wistar rats with simulated kidney dysfunction . MATERIALS AND METHODS. The work was performed on male Wistar rats subjected to 5/6 nephrectomy (NE). The first group after NE received a standard diet (20.16% animal protein ), the second – low protein diet (LPD), including 10% ketosteril . Control rats received a standard diet . After 4 months , blood pressure (BP) and left ventricular mass index (LVMI) were assessed in rats , and a histological examination of the myocardium was performed . In the myocardium , the relative expression levels of NF- kB , miRNA-21, miRNA-133, and miRNA-203 were determined . RESULTS. After 4 months in rats with NE on a standard diet , an increase in blood pressure , an increase in the mass index of the LV myocardium was recorded . MBD with the inclusion of 10% Ketosteril slowed down the growth of systolic blood pressure and the development of LV myocardial hypertrophy in rats with kidney dysfunction . At the histological level , the use of LPD provided a decrease in the degree of hypertrophy of cardiomyocytes and degenerative changes in cardiomyocytes . Animals treated with LPD had less pronounced diffuse and perivascular fibrosis compared with animals fed normal food . The use of MBD slowed down the increase in the relative level of expression of the NFκB gene and miRNA-21 in the myocardium of rats with NE and promoted an increase in the expression level of miRNA-133 and miRNA-203 compared to the indices of animals with NE that received standard food . CONCLUSION: long-term use of LPD with the use of ketoanalogues of essential amino acids can have a potential cardioprotective effect in CKD, slowing down the growth of blood pressure , an increase in LV myocardial mass and the formation of structural changes in the myocardium . It is possible that a decrease in the expression of NF- kB and miRNA-21, as well as an increase in the expression of miRNA-203 and 133 in the myocardium , can play a significant role in this .

Protective Effect of Shengmaiyin in Myocardial Hypertrophy-Induced Rats: A Genomic Analysis by 16S rDNA.

Background The gut-cardiac axis theory provides new insights into the complex mechanisms of cardiac hypertrophy and provides new therapeutic targets. Cardiac hypertrophy is a risk factor for heart failure. Shengmaiyin (SMY) is a traditional Chinese medicine formula with clear effects in the treatment and prevention of cardiac hypertrophy, but the mechanism by which it improves cardiac hypertrophy is still unclear. Therefore, this study aimed to investigate the protective effect and mechanism of SMY on isoproterenol (ISO)-induced myocardial hypertrophy in rats. Methods First, various pharmacodynamic methods were used to evaluate the therapeutic effect of SMY on ISO-induced myocardial hypertrophy in rats. Then, 16S rDNA amplicon sequencing technology was used to study the effect of SMY on the intestinal flora of rats with myocardial hypertrophy. Finally, the mechanism underlying the effect of SMY on cardiac hypertrophy was predicted by bioinformatics network analysis and verified by Western blotting. Results SMY increased ejection fraction (EF%) and left ventricular fractional shortening (FS%), ameliorated myocardial cell injury and fibrosis, regulated blood lipids and energy metabolism, and decreased cardiac hypertrophy marker gene expression. The gut microbiota of ISO-induced myocardial hypertrophy rats were significantly changed, while SMY effectively ameliorated the dysbiosis of the intestinal flora in rats with myocardial hypertrophy, especially Prevotella 9, Lactobacillus, and Clostridium. Mechanistic studies have shown that the anticardiac hypertrophy effect of SMY is related to the inhibition of the expression of HIF1α/PPAR signalling pathway-related proteins. Conclusion SMY significantly improves cardiac function, relieves myocardial cell fibrosis and necrosis, resists cardiac hypertrophy, improves blood lipid metabolism and energy metabolism, regulates intestinal microbial disturbance, and protects the heart.

MTOR INHIBITOR IMPROVES TESTOSTERONE-INDUCED MYOCARDIAL HYPERTROPHY IN HYPERTENSIVE RATS

Objective: Compelling evidence have described the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Our team’s previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mTOR signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. Design and method: For that, ovariectomized (OVX) spontaneously hypertensive rats (SHR) aged 12 weeks were used to study the effects of testosterone (T 2.85 mg/kg/weekly im) on blood pressure and myocardial tissue. On the basis of antihypertensive therapy (chlorthalidone 8 mg/kg/day ig), the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin (0.8 mg/kg/day Vs 1.5 mg/kg/day Vs 2 mg/kg/day ip) in OVX+ estrogens (E 9.6 mg/Kg/day, ig)+T group was further evaluated. Results: After T intervention, the OVX female rats exhibited significant increments in the heart weight / tibial length (TL), cross-sectional area of cardiomyocytes and the mRNA expressions of atrial natriuretic peptide, B- myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and issue inhibitor of metalloproteinase 1. Mammalian rapamycin receptor (mTOR), ribosomal protein S6 kinase (S6K1), 4E-bindiong protein 1(4EBP1) and eukaryotic translation initiation factor 4E in myocardial tissue of OVX+E+T group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of T-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/ S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Conclusions: Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive women with high T levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate T-induced cardiomyocyte hypertrophy.

MTOR inhibitor improves testosterone-induced myocardial hypertrophy in hypertensive rats.

Compelling evidence has described that the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Our team’s previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mammalian rapamycin receptor (mTOR) signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. For that, ovariectomized (OVX) spontaneously hypertensive rats (SHR) aged 12 weeks were used to study the effects of testosterone (T 2.85 mg/kg/weekly i.m.) on blood pressure and myocardial tissue. On the basis of antihypertensive therapy (chlorthalidone 8 mg/kg/day ig), the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin (0.8 mg/kg/day vs 1.5 mg/kg/day vs 2 mg/kg/day i.p.) in OVX + estrogen (E 9.6 mg/kg/day, ig) + testosterone group was further evaluated. After testosterone intervention, the OVX female rats exhibited significant increments in the heart weight/tibial length (TL), area of cardiomyocytes and the mRNA expressions of ANP, β-myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and tissue inhibitor of metalloproteinase 1. mTOR, ribosomal protein S6 kinase (S6K1), 4E-binding protein 1 (4EBP1) and eukaryotic translation initiation factor 4E in myocardial tissue of OVX + estrogen + testosterone group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of testosterone-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive female rats with high testosterone levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate testosterone-induced cardiomyocyte hypertrophy.

Chikusetsu saponin Ⅳa ameliorates myocardial hypertrophy of rats through regulating expression of miR199a-5p/Atg5

The present study investigated the effects of chikusetsu saponin Ⅳa(CHS Ⅳa) on isoproterenol(ISO)-induced myocardial hypertrophy in rats and explored the underlying molecular mechanism. ISO was applied to establish a rat model of myocardial hypertrophy, and CHS Ⅳa(5 and 15 mg·kg~(-1)·d~(-1)) was used for intervention. The tail artery blood pressure was measured. Cardiac ultrasound examination was performed. The ratio of heart weight to body weight(HW/BW) was calculated. Morphological changes in the myocardial tissue were observed by HE staining. Collagen deposition in the myocardial tissue was observed by Masson staining. The mRNA expression of myocardial hypertrophy indicators(ANP and BNP), autophagy-related genes(Atg5, P62 and beclin1), and miR199 a-5 p was detected by qRT-PCR. Atg5 protein expression was detected by Western blot. The results showed that the model group exhibited increased tail artery blood pressure and HW/BW ratio, thickened left ventricular myocardium, enlarged myocardial cells, disordered myocardial fibers with widened interstitium, and a large amount of collagen aggregating around the extracellular matrix and blood vessels. ANP and BNP were largely expressed. Moreover, P62 expression was up-regulated, while beclin1 expression was down-regulated. After intervention by CHS Ⅳa at different doses, myocardial hypertrophy was ameliorated and autophagy activity in the myocardial tissue was enhanced. Meanwhile, miR199 a-5 p expression declined and Atg5 expression increased. As predicted by bioinformatics, Atg5 was a target gene of miR199 a-5 p. CHS Ⅳa was capable of preventing myocardial hypertrophy by regulating autophagy of myocardial cells through the miR-199 a-5 p/Atg5 signaling pathway.

The Protective Effect of Aspirin against Myocardial Hypertrophy in Rats.

The protective effect of aspirin against myocardial hypertrophy (MH) was studied. Model rats of pressure overload MH were prepared by abdominal aortic coarctation. Rats were randomly divided into the sham group (n = 9), MH model group (n = 9), and MH+aspirin group (n = 9), which was, respectively, divided into the 4-week group and 8-week group according to the time of intragastric administration. Arterial blood pressure and left ventricular mass index (LVMI) were measured. Changes in myocardial tissue structure were observed by HE staining, Masson staining, and reticular fiber staining. Cardiomyocyte apoptosis was detected by TUNEL assay. The levels of TNF-α, IL-10, TXA2, and PGI2 in myocardium and plasma were detected by ELISA. The arterial blood pressure in the MH model group was significantly higher than that in the 4- and 8-week sham groups, but that in the MH+aspirin group was significantly lower than that in the MH model group. At 4 and 8 weeks, the LVWI in the MH model group was significantly higher than that in the sham group, but it was significantly reduced after aspirin treatment. The myocardial cell hypertrophy was obvious, collagen fibers were proliferated, and reticular fibers were reduced in the 4- and 8-week MH model groups. Compared with the MH model groups, myocardial cells in the MH+aspirin groups were significantly reduced, the collagen fiber content was significantly reduced, and the reticular fiber content was increased. The apoptotic cardiomyocytes in the 4- and 8-week MH model groups were obviously increased. The apoptosis of myocardial cells in the MH+aspirin groups was obviously decreased. The TNF-α levels in the myocardial tissue of the 4- and 8-week MH model groups were significantly increased, while those of the MH+aspirin groups were significantly decreased. There was no significant change in the IL-10 level or PGI2 level at 4 weeks. At 8 weeks, the PGI2 level was significantly decreased in the MH model group while significantly increased in the MH+aspirin group. The TXA2 levels were significantly increased in the 4- and 8-week MH model groups and those in the 4- and 8-week MH+aspirin groups were significantly lower. Aspirin has an anti-inflammatory effect, can effectively reduce the expression of inflammatory factors, inhibit myocardial apoptosis, and has a certain protective effect against MH.

The CaMKII phosphorylation site Thr1604 in the CaV1.2 channel is involved in pathological myocardial hypertrophy in rats

ABSTRACT Residue Thr1604 in the CaV1.2 channel is a Ca2+/calmodulin dependent protein kinase II (CaMKII) phosphorylation site, and its phosphorylation status maintains the basic activity of the channel. However, the role of CaV1.2 phosphorylation at Thr1604 in myocardial hypertrophy is incompletely understood. Isoproterenol (ISO) was used to induce cardiomyocyte hypertrophy, and autocamtide-2-related inhibitory peptide (AIP) was added as a treatment. Rats in a myocardial hypertrophy development model were subcutaneously injected with ISO for two or three weeks. The heart and left ventricle weights, each of which were normalized to the body weight and cross-sectional area of the myocardial cells, were used to describe the degree of hypertrophy. Protein expression levels were detected by western blotting. CaMKII-induced CaV1.2 (Thr1604) phosphorylation (p-CaV1.2) was assayed by coimmunoprecipitation. The results showed that CaMKII, HDAC, MEF2 C, and atrial natriuretic peptide (ANP) expression was increased in the ISO group and downregulated by AIP treatment in vitro. There was no difference in the expression of these proteins between the ISO 2-week group and the ISO 3-week group in vivo. CaV1.2 channel expression did not change, but p-CaV1.2 expression was increased after ISO stimulation and decreased by AIP. In the rat model, p-CaV1.2 levels and CaMKII activity were much higher in the ISO 3-week group than in the ISO 2-week group. CaMKII-induced CaV1.2 channel phosphorylation at residue Thr1604 may be one of the key features of myocardial hypertrophy and disease development.Abbreviations: CaMKII: Ca2+/calmodulin dependent protein kinase II; p-CaMKII: autophosphorylated Ca2+/calmodulin dependent protein kinase II; CaM: calmodulin; AIP: autocamtide-2-related inhibitory peptide; ECC: excitation-contraction coupling; ISO: isoproterenol; BW: body weight; HW: heart weight; LVW: left ventricle weight; HDAC: histone deacetylase; p-HDAC: phosphorylated histone deacetylase; MEF2C: myocyte-specific enhancer factor 2C; ANP: atrial natriuretic peptide; PKC: protein kinase C

Impacts of a Specific Cyclooxygenase-2 Inhibitor on Pressure Overload-Induced Myocardial Hypertrophy in Rats.

The aim of this study was to observe the impacts of the specific cyclooxygenase-2 inhibitor celecoxib on cardiac structures, functions, and inflammatory factors during the process of pressure overload-induced myocardial hypertrophy. Twenty-four male Sprague Dawley rats were randomly divided into 3 groups: the sham operation group, the surgery group, and the celecoxib group. The model was established according to the abdominal aortic coarctation method. At 16 weeks, rats in the celecoxib group were fed a celecoxib-mixed diet (10 mg/kg) for 8 consecutive weeks. At week 24 after model establishment, the cardiac structures and functions were observed; changes in the levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, prostaglandin E2 (PGE2), C-reactive protein (CRP), and uric acid (UA) were detected; and the contents of Smad1/2/3 proteins (Smad1, Smad2, and Smad3) were determined. Left ventricular mass index, the heart weight/body weight ratio, and TNF-α, TGF-β, PGE2, CRP, and UA levels of the celecoxib group were all significantly decreased relative to those of the surgery group (P < .05); moreover, the cardiac functions were significantly improved compared to those of the surgery group (P < .05). These results show that inflammatory factors are involved in the myocardial hypertrophy process and that celecoxib may reverse myocardial hypertrophy through a variety of pathways.

Myofilament Ca2+ sensitivity correlates with left ventricular contractility during the progression of pressure overload-induced left ventricular myocardial hypertrophy in rats

AimHere we aimed at investigating the relation between left ventricular (LV) contractility and myofilament function during the development and progression of pressure overload (PO)-induced LV myocardial hypertrophy (LVH). MethodsAbdominal aortic banding (AB) was performed to induce PO in rats for 6, 12 and 18 weeks. Sham operated animals served as controls. Structural and molecular alterations were investigated by serial echocardiography, histology, quantitative real-time PCR and western blot. LV function was assessed by pressure-volume analysis. Force measurement was carried out in permeabilized cardiomyocytes. ResultsAB resulted in the development of pathological LVH as indicated by increased heart weight-to-tibial length ratio, LV mass index, cardiomyocyte diameter and fetal gene expression. These alterations were already present at early stage of LVH (AB-week6). Furthermore, at more advanced stages (AB-week12, AB-week18), myocardial fibrosis and chamber dilatation were also observed. From a hemodynamic point of view, the AB-wk6 group was associated with increased LV contractility, maintained ventriculo-arterial coupling (VAC) and preserved systolic function. In the same experimental group, increased myofilament Ca2+ sensitivity (pCa50) and hyperphosphorylation of cardiac troponin-I (cTnI) at Threonine-144 was detected. In contrast, in the AB-wk12 and AB-wk18 groups, the initial augmentation of LV contractility, as well as the increased myofilament Ca2+ sensitivity and cTnI (Threonine-144) hyperphosphorylation diminished, leading to impaired VAC and reduced systolic performance. Strong correlation was found between LV contractility parameters and myofilament Ca2+-sensitivity among the study groups. ConclusionChanges in myofilament Ca2+ sensitivity might underlie the alterations in LV contractility during the development and progression of PO-induced LVH.

PO-173 The Effects of Interval Exercise on oxidative stress and Smyd1-related myocardial hypertrophy in Rats with Myocardial Infarction

Objective This study was carried out to investigate interval exercise on Smyd1 expression and F-actin sarcomere assembly in non-infarcted myocardium of normal and myocardial infarction(MI) rats and its possible mechanism.&#x0D; Methods Male SD rats were randomly divided into normal control group (C), normal interval exercise group (CE), sham-operated group (S), MI group (MI), MI with interval exercise group (ME) and MI with ROS Tempol group (MT), n=10. MI model was established by left anterior descending coronary artery ligation. Interval exercise was carried out on a small animal treadmill. MT group was given an oral solution of Tempol (2mmol/L). Hemodynamics was performed to evaluate cardiac function. HE and Masson staining were used to analyze the cross-sectional area (CSA) of cardiomyocytes and collagen volume fraction, respectively. T-SOD and MDA kits were used to detect oxidative stress. H9C2 cells were treated with H2O2. Immunofluorescence staining was used to determine Smyd1 expression and F-actin sarcomere assembly. RT-qPCR and Western blotting were used to detect the gene or protein expression of Smyd1, Trx1, Hsp90, MuRF1, cTnI, α-actinin and BNP.&#x0D; Results Smyd1, Trx1, Hsp90, MuRF1 and BNP expression in the peri-infarcted area were up-regulated, but cTnI and α-actinin expression and F-actin assembly were decreased. The cardiac function was reduced. Both interval exercise and Tempol intervention significantly increase the CSA and expression of Smyd1, Trx1, cTnI and α-actinin, improve the antioxidation capacity and F-actin sarcomere assembly and cardiac function, reduce the expression of Hsp90, MuRF1, BNP and ROS level, and inhibit the fibrosis of myocardium. The oxidative stress level was closely related to the Smyd1 expression. Improvement of cardiac function were correlated with Smyd1 expression. H2O2 can induce oxidative stress injuries of H9C2, and its closely related to cardiomyocytes oxidative stress level and Smyd1 expression.&#x0D; Conclusions Interval exercise could promote antioxidant capability and physiological cardiomyocyte hypertrophy, regulate the expression of Smyd1, Hsp90 and MuRF1 in infarcted heart; so as to improve the cardiac function. Smyd1 may participate in pathologic hypertrophy of cardiomyocytes caused by oxidative stress.

Protective effect of Dendrobium candidum on isoproterenol induced cardiac hypertrophy in rats

To study the effect and mechanism of Dendrobium candidum on isoproterenol-induced myocardial hypertrophy in rats, 60 healthy SD rats(30 males and 30 females) were randomly divided into 5 groups(12 in each group): normal group, model group, three D. candidum preventive administration groups(0.09, 0.18, 1.1 g·kg⁻¹). Except for the normal group, rats of other groups were injected back subcutaneously with ISO(5 mg·kg⁻¹) for 10 consecutive days. At the same time, preventive administration groups began to give different doses of the sample for 30 days and model group began to give normal saline. Left ventricular systolic pressure(LVSP) was measured in each group by common carotid artery cannulation, and the left ventricle(LW)/tibia length, heart weight index(HWI) and myocardial hydroxyproline(Hydro) content were calculated. Myocardial tissue HE staining and Masson staining were used to observe the myocardial structure and the degree of myocardial fibrosis respectively. Atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP), and cardiac troponin I(cTN-I) concentration were measured by enzyme-linked immunosorbent assay(ELISA). The results showed that as compared with the normal group, the levels of ANP, BNP and cTN-I in plasma were significantly increased in ISO-induced hypertrophic rats; as compared with the model group, D. candidumcan inhibit ISO-induced ventricular pressure and ventricular hypertrophy, reduce myocardial collagen synthesis, improve myocardial fibrosis and ventricular remodeling, and significantly down-regulate ANP, BNP and cTN-I levels in plasma. This study shows that D. candidum has a protective effect on isoproterenol-induced cardiac hypertrophy.

Omega-3-fatty acid adds to the protective effect of flax lignan concentrate in pressure overload-induced myocardial hypertrophy in rats via modulation of oxidative stress and apoptosis

Objective of the present investigation was to study the effect of the flax lignan concentrate (FLC) and Omega-3-fatty acid (O-3-FA) on myocardial apoptosis, left ventricular (LV) contractile dysfunction and electrocardiographic abnormalities in pressure overload-induced cardiac hypertrophy. The rats were divided into five groups such as sham, aortic stenosis (AS), AS+FLC, AS+O-3-FA and AS+FLC+O-3-FA. Cardiac hypertrophy was produced in rats by abdominal aortic constriction. The rats were treated with FLC (400mg/kg, p.o.), O-3-FA (400mg/kg, p.o.) and FLC+O-3-FA orally per day for four weeks. The LV function, myocardial apoptosis, and oxidative stress were quantified. FLC+O-3-FA treatment significantly reduced hemodynamic changes, improved LV contractile dysfunction, reduced cardiomyocyte apoptosis and cellular oxidative stress. Moreover, it significantly up-regulated the VEGF expression and decreased TNF-alpha level in serum. The histological analysis also revealed that FLC+O-3-FA treatment markedly preserved the cardiac structure and inhibited interstitial fibrosis. In conclusion, FLC+O-3-FA treatment improved LV dysfunction, inhibited cardiomyocyte apoptosis, improved myocardial angiogenesis, conserved activities of membrane-bound phosphatase enzymes and suppressed inflammation through reduced oxidative stress in an additive manner than FLC alone and O-3-FA alone treatment in pressure overload-induced cardiac hypertrophy.

Hydrogen sulfide endothelin-induced myocardial hypertrophy in rats and the mechanism involved.

The aim of the study was to evaluate the clinical efficacy of hydrogen sulfide (H2S) treatment on the endothelin-induced cardiac hypertrophy. Sixty-four adult male rats, weighing from 180 to 200 g, were randomly divided into four groups: ten in normal group, ten in sham group, 44 in model group established by inducing the myocardial hypertrophy with endothelin. The myocardial hypertrophy model rats were randomly divided into two groups: 22 in the simple myocardial hypertrophy model group and 22 in the H2S treatment group. Rats in normal group were given 2 ml pure water by gavage per day, those in the sham group and simple cardiac hypertrophy model group were given 2 ml of saline by gavage per day, and rats in the pure cardiac hypertrophy with H2S treatment were given intraperitoneal injections of 2 ml NaHS saline per day for a period of 4 weeks. Left ventricular mass index, myocyte hypertrophy, volume fraction of myocardial interstitial collagen, myocardial hydroxyproline content and other indicators of cardiac hypertrophy were observed after 4 weeks. (1) There were significant differences on the ventricular mass between the treatment group and the cardiac hypertrophy group: The left ventricular mass decreased 21.4 % and the left ventricular mass index decreased 5.97 % (P < 0.05; (2) the smallest cardiomyocytes diameter and cardiomyocytes cross-sectional area decreased 12.5 and 10.8 %, respectively (P < 0.05) in the treatment group compared to the cardiac hypertrophy group; (3) the volume fraction of myocardial interstitial collagen and the myocardial hydroxyproline content decreased 22.3 and 31.3 % in treatment group compared with the cardiac hypertrophy group, respectively (P < 0.05). H2S had a good clinical efficacy in reducing left ventricular mass fraction and myocardial collagen levels, improving myocardial hypertrophy and decrease myocardial fibrosis. It is worthy for further clinical studies.

Adrenomedullin protects against fructose-induced insulin resistance and myocardial hypertrophy in rats

Adrenomedullin (ADM) has been recognized as a multipotent multifunctional peptide. To explore the pathophysiological roles of ADM in insulin resistance (IR), we studied the changes in ADM mRNA level in the myocardium and vessels and the effect of ADM supplementation on rats with IR induced by fructose feeding. Rats were fed 4% fructose in drinking water for 8 weeks, and ADM was administered subcutaneously in pure water through an Alzet Mini-osmotic Pump at 300ng/kg/h for the last 4 weeks. Compared with controls, rats with IR showed increased levels of fasting blood sugar and serum insulin, by 95% and 67%, respectively (all P<0.01), and glycogen synthesis and glucose transport activity of the soleus decreased by 54% and 55% (all P<0.01). mRNA level and content of brain natriuretic peptide (BNP) in myocardial were all increased significantly. Fructose-fed rats showed increased immunoreactive-ADM content in plasma by 110% and in myocardia by 55% and increased mRNA level in myocardia and vessels (all P<0.01). ADM administration ameliorated the induced IR and myocardial hypertrophy. The glycogen synthesis and glucose transport activity of the soleus muscle increased by 41% (P<0.01) and 32% (P<0.05). ADM therapy attenuated myocardial and soleus lipid peroxidation injury and enhanced the antioxidant ability. Our results showed upregulation of endogenous ADM during fructose-induced IR and the protective effect of ADM on fructose-induced IR and concomitant cardiovascular hypertrophy probably by its antioxidant effect, which suggests that ADM could be an endogenous protective factor in IR.

Angiotensin-II type 1 receptor and NOX2 mediate TCF/LEF and CREB dependent WISP1 induction and cardiomyocyte hypertrophy

Angiotensin-II (Ang-II) plays a key role in myocardial hypertrophy, remodeling and failure. We investigated whether Ang-II-induced cardiomyocyte hypertrophy is dependent on WNT1 inducible signaling pathway protein 1 (WISP1), a pro growth factor. Ang-II induced hypertrophy and WISP1 expression in neonatal rat cardiomyocytes (NRCM), effects that were significantly inhibited by pre-treatment with the AT1 antagonist losartan and by WISP1 knockdown. Further, Ang-II induced WISP1 was superoxide-dependent, and inhibited by DPI, an inhibitor of NADPH oxidases, and by knockdown of NOX2. AT1 was physically associated with NOX2 both in vitro and in vivo, and Ang-II increased this interaction in vivo. Ang-II induced WISP1 expression via superoxide/Akt/GSK3β/β-catenin/TCF/LEF and by Akt-dependent CREB activation. Further, Ang-II also activated CREB via superoxide-mediated p38 MAPK and ERK activation. Continuous infusion of Ang-II for 7days induced myocardial hypertrophy in rats, and was associated with increased Akt, p-Akt, p-p38 MAPK, p-ERK1/2, and WISP1 expression. These results demonstrate that Ang-II induced cardiomyocyte hypertrophy is mediated through AT1, NOX2 and the induction of WISP1, and may involve the direct interaction of AT1 with NOX2. Thus targeting both WISP1 and NOX2 may have a therapeutic potential in improving cardiomyocyte survival and growth following myocardial injury and remodeling. This article is part of a Special Issue entitled ‘Possible Editorial’.

The Time Constant of Left Ventricular Relaxation

Left ventricular (LV) diastolic dysfunction induces the increase of LV diastolic pressure and subsequently of left atrial and pulmonary capillary pressures independent of systolic function, resulting in the onset of heart failure. In the early 1990s, several clinical studies demonstrated that diastolic dysfunction is an independent prognostic factor in patients with heart failure with reduced ejection fraction (EF).1,2 In the past decade, many clinical studies have clarified that heart failure with preserved EF (HFPEF) accounts for ≈40% of heart failure and that its prognosis is as poor as heart failure with reduced EF.3 With the growing interest in HFPEF, the important role of diastolic dysfunction in the pathogenesis of heart failure has been realized again, because it is plausible that LV diastolic dysfunction is one of the principal causes for this phenotype of heart failure.4 Article see p 268 Major determinants of LV diastolic function are relaxation and stiffness.5 Despite the clinical requisite for their evaluation in understanding the pathophysiology of each patient with heart failure, there are no established indices for the noninvasive assessment of these factors. An invasive measure of LV pressure is required for the evaluation of LV relaxation, and the simultaneous recording of LV pressure and geometry is necessary for the assessment of LV stiffness. LV relaxation abnormality is likely to precede LV stiffening or systolic dysfunction during the development of chronic heart failure and has been assigned as a sensitive sign of LV dysfunction. Peak negative value of the first derivative of LV pressure (peak−dP/dt) has been used as a quantitative index for LV relaxation, but it depends on many other hemodynamic and functional factors. Weiss et al6 showed that the time course of isovolumic pressure decrease subsequent to peak−dP/dt is exponential and proposed the time …

Correlation between plasma levels of apelin and myocardial hypertrophy in rats and humans: possible target for treatment?

Objective: To investigate the effects of left ventricular (LV) pressure overload and diabetes on the apelinergic system. Research design/methods: Pressure overload was established in rats by supra-renal aortic-banding. Six weeks later, diabetes was induced by streptozotocin (65 mg/kg, intraperitoneal), resulting in four groups: sham, banded (BA), diabetic (DM) and diabetic-banded (DM-BA). Twelve weeks later, LV function and structure were evaluated by echocardiography and biopsies and plasma samples collected. Furthermore, plasma samples and LV-endomyocardial biopsies were procured from aortic stenosis and mitral stenosis patients during surgery to evaluate myocardial expression of apelin and APJ-receptor and plasma levels of apelin. Results: Direct correlations between apelin plasma levels and LV-mass index and between apelin and APJ myocardial expression were observed both in humans and rats. Expression of apelin and APJ was not significantly altered by pressure-overload in humans, being downregulated by pressure overload and even more by diabetes in rats. Finally, an inverse correlation between apelin rat plasma levels and its myocardial expression was observed. Conclusions: While apelin/APJ myocardial expression decreases, apelin plasma levels increase in LV hypertrophy. Considering apelin's positive inotropic and vasodilator properties, this elevation in apelin plasma levels may represent a compensatory mechanism to maintain inotropism and cardiac output during pressure-overload or diabetic cardiomyopathy.

Carbon Monoxide

Carbon Monoxide