Left Ventricular Weight To Body Weight Research Articles

Astragaloside IV for Heart Failure: Preclinical Evidence and Possible Mechanisms, A Systematic Review and Meta-Analysis.

To explore the cardioprotective effects of astragaloside IV (AS-IV) in heart failure (HF). PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Web of Science, Wanfang Database, Chinese Bio-medical Literature and Retrieval System (SinoMed), China Science and Technology Journal Database (VIP), and China National Knowledge Infrastructure (CNKI) were searched from inception to November 1, 2021 for animal experiments to explore AS-IV in treating HF in rats or mice. The left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), left ventricular weight-to-body weight (LVW/BW) and B-type brain natriuretic peptide (BNP) were recorded. The qualities of included studies were assessed by the risk of bias according to the Cochrane handbook. Meta-analysis was performed using Stata 13.0. Twenty-one articles involving 558 animals were considered. Compared with the control group, AS-IV improved cardiac function, specifically by increasing LVEF (mean difference (MD)=6.97, 95% confidence interval (CI)=5.92 to 8.03, P<0.05; fixed effects model) and LVFS (MD=7.01, 95% CI=5.84 to 8.81, P<0.05; fixed effects model), and decreasing LVEDD (MD=-4.24, 95% CI=-4.74 to -3.76, P<0.05; random effects model) and LVESD (MD=-4.18, 95% CI=-5.26 to -3.10, P<0.05; fixed effects model). In addition, the BNP and LVW/BW levels were decreased in the AS-IV treatment group (MD=-9.18, 95% CI=-14.13 to -4.22, P<0.05; random effects model; MD=-1.91, 95% CI=-2.42 to -1.39, P<0.05; random effects model). AS-IV is a promising therapeutic agent for HF. However, this conclusion needs to be clinically validated in the future.

A Reduction in ADAM17 Expression Is Involved in the Protective Effect of the PPAR-α Activator Fenofibrate on Pressure Overload-Induced Cardiac Hypertrophy.

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist fenofibrate ameliorates cardiac hypertrophy; however, its mechanism of action has not been completely determined. Our previous study indicated that a disintegrin and metalloproteinase-17 (ADAM17) is required for angiotensin II-induced cardiac hypertrophy. This study aimed to determine whether ADAM17 is involved in the protective action of fenofibrate against cardiac hypertrophy. Abdominal artery constriction- (AAC-) induced hypertensive rats were used to observe the effects of fenofibrate on cardiac hypertrophy and ADAM17 expression. Primary cardiomyocytes were pretreated with fenofibrate (10 μM) for 1 hour before being stimulated with angiotensin II (100 nM) for another 24 hours. Fenofibrate reduced the ratios of left ventricular weight to body weight (LVW/BW) and heart weight to body weight (HW/BW), left ventricular anterior wall thickness (LVAW), left ventricular posterior wall thickness (LVPW), and ADAM17 mRNA and protein levels in left ventricle in AAC-induced hypertensive rats. Similarly, in vitro experiments showed that fenofibrate significantly attenuated angiotensin II-induced cardiac hypertrophy and diminished ADAM17 mRNA and protein levels in primary cardiomyocytes stimulated with angiotensin II. In summary, a reduction in ADAM17 expression is associated with the protective action of PPAR-α agonists against pressure overload-induced cardiac hypertrophy.

Xinfuli Granule improves post-myocardial infarction ventricular remodeling and myocardial fibrosis in rats by regulating TGF-β/Smads signaling pathway.

BackgroundRecent clinical and experimental studies have confirmed the effects of Xinfuli Granule (XG), a compound Chinese medicine in the prevention and treatment of heart failure (HF). This study aimed to investigate the effects and the mechanisms of XG on ventricular reconstruction in rats with acute myocardial infarction (AMI).MethodsSprague-Dawley rats were subjected to left anterior descending branch ligation. The rats that survived 24 h were randomly assigned to five groups: medium-dose of XG group (MI+XGM), high-dose of XG group (MI+XGH), carvedilol group (MI+C), medium-dose of XG + carvedilol group (MI+C+XGM). Fourteen rats underwent identical surgical procedures without artery ligation, serving as sham controls. At 28 days, left ventricular weight to body weight (LVW/BW) and heart weight to body weight (HW/BW) were calculated; left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVFS), left ventricular internal diameter at systole (LVIDS) were measured by ultrasound; HE staining, Masson staining, and Sirius red staining were used to assess the myocardial pathological and physiological changes as well as myocardial fibrosis area and non-infarct zone I/III collagen ratio. Expression of Smad3 were detected and analyzed by Western blot, immunohistochemistry and immunofluorescence. P-Smad3, Smad2 and Smad7 in the TGF-β/Smads signaling pathway were also analyzed by Western blot.ResultsThe LVIDS (P < 0.01), HW/BW (P < 0.05), type I/III collagen ratio (P < 0.01) and myocardial collagen (P < 0.01) decreased significantly while the LVW/BW, LVFS (P < 0.05) increased significantly in MI+XGM group as compared with those in other groups. The expression of key signal molecules of the TGF-β/Smads signaling pathway, including Smad3, P-Smad3 and Smad2 protein were decreased, while the expression of Smad7 increased in both XG and carvedilol treatment groups as compared to those of the MI group (all P < 0.01). Immunohistochemistry and immunofluorescence further confirmed the down-regulated Smad3 expression.ConclusionXG can improve ventricular reconstruction and inhibit myocardial fibrosis in rats with AMI by regulating TGF-β/Smads signaling pathway.

Abstract 427: Micrornas Have Differential Degree of Expression in Pathological Cardiac Hypertrophy Compared to Physiological Cardiac Hypertrophy

Physiological and pathological left ventricular hypertrophies (LVH) are distinct processes that have differential pattern of gene expression. Based on initial stimuli, miRs expression levels can fluctuate and then cause a variance on their targets culminating in diverse cellular pathway activation. AIM: Here we compared miRs expression between pathological cardiac hypertrophy induced by transverse aortic constriction (TAC) and physiological cardiac hypertrophy induced by voluntary exercise in running wheels (EXE). METHODS: Adult male Balb/c mice (12-14 weeks old) mice were subjected to TAC or EXE protocol and data were evaluated at 7 (TAC-7D; EXE-7D) and 35 (TAC-35D; EXE-35D) days. Hypertrophy was measured by normalizing left ventricular weight to body weight (LVW/BW). We evaluated left ventricular expression levels of miRs: -26b, 27a, -143, -150, -195 and -499 by qRT-PCR in TAC and EXE groups. Comparisons between groups were performed by ANOVA with Bonferroni correction. Results are shown as mean±SEM. Results: Sedentary and Sham groups were similar among all variables tested. Animals subjected to TAC surgery demonstrated a greater hypertrophy than EXE animals at both time points (7D: 16% vs. 7%; 35D 26% vs 12%, p&lt;0.05 for both). MiR-26b had increased levels in TAC group at both time points (7D: 1.14±0.1 vs 0.6±0.01; 35D: 4.8±1.4 vs 1.17±0.12; p&lt;0.01 for both). We only detected an increase in miR-27a levels in TAC-7D compared to EXE-7D (2.7±1.0 vs 0.78±0.1, p &lt;0.05). We identified an augmentation in miR-143 levels in TAC group at both time points (7D: 1.1±0.1 vs 0.75±0.1; 35D: 1.42±0.2 vs 0.9±0.1; p&lt;0.05 for both). We detected an increase in miR-499 levels at both time points in TAC group (7D: 4.1±0.5 vs 0.67±0.2, p&lt;0.001; 35D: 2.2±0.4 vs 0.9±0.2, p&lt;0.01). We found an increase in miR-195 levels only in TAC-35D group compared to EXE-35D (2.6±0.3 vs 0.9±0.1, p&lt;0.05). We did not notice any change in miR-150 levels neither at 7 days nor at 35 days. Conclusions: These preliminary data demonstrate a differential degree of miR expression between physiological and pathological hypertrophy. Further studies comparing physiological and pathological cardiac hypertrophy are necessary to find out the turning point that deviates heart from adaptive to maladaptive growth.

Puerarin Suppresses Angiotensin II-Induced Cardiac Hypertrophy by Inhibiting NADPH Oxidase Activation and Oxidative Stress-Triggered AP-1 Signaling Pathways.

To examine the effects of puerarin (Pue) on angiotensin II (AngII)-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and oxidative stress-related signaling pathways in the hypertrophic response of cardiomyocytes. Primary cardiomyocytes of neonatal C57BL/6J mice were pretreated with Pue (50, 100 μmol/L) and were then stimulated with AngII 1 μmol/L. NADPH oxidase activity and reactive oxygen species (ROS) levels were measured by lucigenin-enhanced chemiluminescence assay and flow cytometry. Western blotting was used to detect the distribution of the oxidase subunits, extracellular signal-regulated kinase (ERK1/2) and c-jun N-terminal kinase (JNK1/2) activation, and an electrophoretic mobility shift assay (EMSA) was performed to analyze the DNA binding activity of activator protein-1 (AP-1). Adult C57BL/6J mice were infused with AngII and were administered with Pue (100, 200 mg·kg-1·d-1) for 15 d. After the treatment, systolic blood pressure (SBP) and left ventricular wall thickness were examined. The ratios of heart weight to body weight (HW/BW) and left ventricular weight to body weight (LVW/BW) were measured, and heart morphometry was assessed. In vitro, Pue dose-dependently blocked the phosphorylation of ERK1/2 and JNK1/2 and eventually abolished AP-1 binding activity through the inhibition of ROS production. Further studies revealed that AngII treatment resulted in increased NADPH oxidase activity, which was suppressed by Pue via the disruption of Rac1 activation and membrane translocation of oxidase subunits. In vivo, Pue attenuated cardiac hypertrophy, as evaluated by decreased HW/BW, LVW/BW, myocyte surface area, and left ventricular wall thickness. The anti-hypertrophic mechanism of Pue occurred by blocking Rac1-dependent NADPH oxidase activation and downstream redox-sensitive AP-1 signaling pathways.

Puerarin inhibits angiotensin II-induced cardiac hypertrophy via the redox-sensitive ERK1/2, p38 and NF-κB pathways

To investigate the effects of puerarin (Pue), an isoflavone derived from Kudzu roots, on angiotensin II (Ang II)-induced hypertrophy of cardiomyocytes in vivo and in vitro. C57BL/6J mice were infused with Ang II and treated with Pue (100 mg·kg(-1)·d(-1), po) for 15 d. After the treatment, systolic blood pressure (SBP) and left ventricular wall thickness were assessed. The ratios of heart weight to body weight (HW/BW) and left ventricular weight to body weight (LVW/BW) were determined, and heart morphometry was assessed. Expression of fetal-type genes (ANP, BNP and β-MHC) in left ventricles was measured using semi-quantitative RT-PCR. Mouse primary cardiomyocytes were treated with Pue (50, 100, 200 μmol/L), then exposed to Ang II (1 μmol/L). ROS level was examined with flow cytometry, the binding activity of NF-κB was determined using EMSA. Western blot was used to measure the levels of ERK1/2, p38 and NF-κB pathway proteins. [(3)H]leucine incorporation was used to measure the rate of protein synthesis. Oral administration of Pue significantly suppressed Ang II-induced increases in the myocyte surface area, HW/BW, LVW/BW, SBP and left ventricular wall thickness. Furthermore, Pue significantly suppressed Ang II-induced increases in ANP, BNP and β-MHC expression in the left ventricles in vivo. Treatment of cardiomyocytes with Pue (50-500 μmol/L) did not affect the viability of cardiomyocytes in vitro. Pretreatment of cardiomyocytes with Pue dose-dependently inhibited Ang II-induced increases in ROS production, NF-κB binding activity, protein synthesis and cell breadth. Furthermore, pretreatment with Pue significantly suppressed Ang II-induced activation of ERK1/2, p38 and the NF-κB pathway proteins and the expression of ANP and β-MHC in cardiomyocytes. The positive drug valsartan exerted similar effects on Ang II-induced cardiac hypertrophy in vivo and in vitro. Pue attenuates Ang II-induced cardiac hypertrophy by inhibiting activation of the redox-sensitive ERK1/2, p38 and the NF-κB pathways.

EPLERENONE ATTENUATES MYOCARDIAL FIBROSIS IN THE ANGIOTENSIN II-INDUCED HYPERTENSIVE MOUSE: INVOLVEMENT OF OSTEOPOTIN INDUCED BY NADPH OXIDASE

EPLERENONE ATTENUATES MYOCARDIAL FIBROSIS IN THE ANGIOTENSIN II-INDUCED HYPERTENSIVE MOUSE: INVOLVEMENT OF OSTEOPOTIN INDUCED BY NADPH OXIDASE

Propranolol enhances cell cycle-related gene expression in pressure overloaded hearts

Cell cycle regulators are regarded as essential for cardiomyocyte hypertrophic growth. Given that the β-adrenoceptor antagonist propranolol blunts cardiomyocyte hypertrophic growth, we determined whether propranolol alters the expression of cell cycle-related genes in mouse hearts subjected to pressure overload. Pressure overload was induced by transverse aortic constriction (TAC), whereas the expression levels of 84 cell cycle-related genes were assayed by real-time PCR. Propranolol (80 mg·kg(-1) ·day(-1) ) was administered in drinking water for 14 days. Two weeks after surgery, TAC caused a 46% increase in the left ventricular weight-to-body weight (LVW/BW) ratio but no significant changes in cell cycle gene expression. Propranolol, at plasma concentrations ranging from 10 to 140 ng·mL(-1) , blunted the LVW/BW ratio increase in TAC mice, while significantly increasing expression of 10 cell cycle genes including mitotic cyclins and proliferative markers such as Ki67. This increase in cell cycle gene expression was paralleled by a significant increase in the number of Ki67-positive non-cardiomyocyte cells as revealed by immunohistochemistry and confocal microscopy. β-Adrenoceptor signalling was critical for cell cycle gene expression changes, as genetic deletion of β-adrenoceptors also caused a significant increase in cyclins and Ki67 in pressure overloaded hearts. Finally, we found that metoprolol, a β(1) -adrenoceptor antagonist, failed to enhance cell cycle gene expression in TAC mice. Propranolol treatment enhances cell cycle-related gene expression in pressure overloaded hearts by increasing the number of cycling non-cardiomyocyte cells. These changes seem to occur via β(2) -adrenoceptor-mediated mechanisms.

Resistin Promotes Cardiac Hypertrophy via the AMP-activated Protein Kinase/Mammalian Target of Rapamycin (AMPK/mTOR) and c-Jun N-terminal Kinase/Insulin Receptor Substrate 1 (JNK/IRS1) Pathways

Resistin has been suggested to be involved in the development of diabetes and insulin resistance. We recently reported that resistin is expressed in diabetic hearts and promotes cardiac hypertrophy; however, the mechanisms underlying this process are currently unknown. Therefore, we wanted to elucidate the mechanisms associated with resistin-induced cardiac hypertrophy and myocardial insulin resistance. Overexpression of resistin using adenoviral vector in neonatal rat ventricular myocytes was associated with inhibition of AMP-activated protein kinase (AMPK) activity, activation of tuberous sclerosis complex 2/mammalian target of rapamycin (mTOR) pathway, and increased cell size, [(3)H]leucine incorporation (i.e. protein synthesis) and mRNA expression of the hypertrophic marker genes, atrial natriuretic factor, brain natriuretic peptide, and β-myosin heavy chain. Activation of AMPK with 5-aminoimidazole-4-carbozamide-1-β-D-ribifuranoside or inhibition of mTOR with rapamycin or mTOR siRNA attenuated these resistin-induced changes. Furthermore, resistin increased serine phosphorylation of insulin receptor substrate (IRS1) through the activation of the apoptosis signal-regulating kinase 1/c-Jun N-terminal Kinase (JNK) pathway, a module known to stimulate insulin resistance. Inhibition of JNK (with JNK inhibitor SP600125 or using dominant-negative JNK) reduced serine 307 phosphorylation of IRS1. Resistin also stimulated the activation of p70(S6K), a downstream kinase target of mTOR, and increased phosphorylation of the IRS1 serine 636/639 residues, whereas treatment with rapamycin reduced the phosphorylation of these residues. Interestingly, these in vitro signaling pathways were also operative in vivo in ventricular tissues from adult rat hearts overexpressing resistin. These data demonstrate that resistin induces cardiac hypertrophy and myocardial insulin resistance, possibly via the AMPK/mTOR/p70(S6K) and apoptosis signal-regulating kinase 1/JNK/IRS1 pathways.

Signaling pathway-focused gene expression profiling in pressure overloaded hearts.

The β-blocker propranolol displays antihypertrophic and antifibrotic properties in the heart subjected to pressure overload. Yet the underlying mechanisms responsible for these important effects remain to be completely understood. The purpose of this study was to determine signaling pathway-focused gene expression profile associated with the antihypertrophic action of propranolol in pressure overloaded hearts. To address this question, a focused real-time PCR array was used to screen left ventricular RNA expression of 84 gene transcripts representative of 18 different signaling pathways in C57BL/6 mice subjected to transverse aortic constriction (TAC) or sham surgery. On the surgery day, mice received either propranolol (80 mg/kg/day) or vehicle for 14 days. TAC caused a 49% increase in the left ventricular weight-to-body weight (LVW/BW) ratio without changing gene expression. Propranolol blunted LVW/BW ratio increase by approximately 50% while causing about a 3-fold increase in the expression of two genes, namely Brca1 and Cdkn2a, belonging to the TGF-beta and estrogen pathways, respectively. In conclusion, after 2 weeks of pressure overload, TAC hearts show a gene expression profile superimposable to that of sham hearts. Conversely, propranolol treatment is associated with an increased expression of genes which negatively regulate cell cycle progression. It remains to be established whether a mechanistic link between gene expression changes and the antihypertrophic action of propranolol occurs.

Age-related up-regulation of β3-adrenergic receptor in heart-failure rats

Stimulation of β1- and β2-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the β3-AR is also expressed in the heart and that its stimulation leads to negative inotropic effects. The aim of this study was to investigate the expression of β3-AR in age-related heart-failure rats and its relevance to left ventricular dysfunction. Aging male Wistar rats were divided into young and aging groups according to age, and each group included sham-operation and heart-failure subgroups. Left ventricular end-diastolic pressure (LVEDP) and the ratio of left ventricular weight to body weight (LV/BW) were significantly higher for the aging heart-failure versus young heart-failure and the heart-failure versus sham-operation groups (P < 0.01, respectively). However, the left ventricular end-systolic pressure (LVESP) and the maximal rate of rise or fall of left ventricular pressure were all significantly lower for the aging heart-failure versus young heart-failure and the heart-failure versus sham-operation groups (P < 0.01, respectively). β3-AR protein levels increased significantly when heart failure worsened in aging rats. These results suggest that β3-AR expression in age-related heart-failure rats and left ventricular function were highly correlated.

Effects of high thoracic epidural anesthesia on ventricular remodeling and expression of beta(3)-adrenoceptor in rats with heart failure induced by acute myocardial infarction

To investigate the effect of high thoracic epidural anesthesia on ventricular remodeling and cardiac function in rats with heart failure induced by myocardial infarction, and to investigate their mechanism. Rats that had been established successively model were randomly divided into S group (n = 12), HTEA group and CHF group (24/group). 9.0 g/L normal sodium 100 microl/kg was injected to epidural cavity twice a day separately in group S and group CHF. 1.25 g/L bupivacaine 100 microl/kg was injected to epidural cavity twice a day in group HTEA. Epidural injection was started 24 hrs after the epidural surgery and continued 4 weeks. Then the change of cardiac function was observed by using echocardiogram. The ratio of heart weight to body weight (HW/BW) and the ratio of left ventricular weight to body weight (LVW/BW) were measured. Noninfarct ventricular tissue were stained with hematoxylin-eosin (HE) and Masson's trichrome respectively. beta(3)-adrenoceptor levels and eNOS levels were detected with reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. LVEDD and LVESD were significantly decreased in the group HTEA compared with group CHF (P < 0.01), while LVEF% and LVFS% were significantly increased (P < 0.01). The ratios HW/BW and LVW/BW were significantly increase in the group CHF compared with the group S (P < 0.01), but they were limited in the group HTEA (P < 0.01). Hypertrophy and edema, degeneration and necrosis of myocytes can be seen in rats with CHF, as well as muscle fibers disruption and collagen fiber increase, while the pathological amorphous were attenuated in HTEA rats. beta(3)AR and eNOS mRNA levels were significantly decreased in the group THEA compared with the group CHF. These results indicate that HTEA could ameliorate ventricular remodeling and cardiac function in rats with heart failure induced by myocardial infarction. The mechanism could involve decreases of beta(3)AR expression in rats of heart failure.

Effect of Mast Cell Stabilizers in Hyperhomocysteinemia-induced Cardiac Hypertrophy in Rats

The present study has been designed to investigate the effect of sodium cromoglycate and ketotifen, mast cell stabilizers in hyperhomocysteinemia-induced cardiac hypertrophy in rats. Rats were administered L-methionine (1.7 g/kg/day PO) for 8 weeks to produce hyperhomocysteinemia. Sodium cromoglycate (24 mg/kg/day IP) and ketotifen (1mg/kg/day IP) treatments were started from first day of administration of L-methionine and continued for 8 weeks. The development of cardiac hypertrophy was assessed in terms of measuring mean arterial blood pressure (MABP), ratio of left ventricular (LV) weight to body weight (LVW/BW), LV wall thickness (LVWT), LV protein content, and LV collagen content. Further, the oxidative stress in heart was assessed by measuring lipid peroxidation, superoxide anion generation, and reduced glutathione (GSH). Moreover, the cardiomyocyte diameter and LV mast cell density were determined using hematoxylin-eosin and toluidine blue staining, respectively. The L-methionine administration produced hyperhomocysteinemia, which significantly increased MABP, oxidative stress, and density of mast cells and consequently produced cardiac hypertrophy by increasing cardiomyocyte diameter, LVW/BW, LVWT, LV protein and collagen content. However, sodium cromoglycate and ketotifen treatments significantly attenuated hyperhomocysteinemia-induced oxidative stress and pathological cardiac hypertrophy without significantly altering MABP. Moreover, sodium cromoglycate and ketotifen treatments did not affect serum homocysteine levels. Thus, it may be concluded that hyperhomocysteinemia-induced cardiac hypertrophy is associated with an increase in oxidative stress and density of mast cells in heart. Sodium cromoglycate and ketotifen may have attenuated hyperhomocysteinemia-induced pathological cardiac hypertrophy, possibly by reducing oxidative stress and preventing the degranulation and increase in density of mast cells.

Chronic blocking of β3-adrenoceptor ameliorates cardiac function in rat model of heart failure

Stimulation of the heart beta 3-adrenoceptor (AR) may result in a negative inotropic effect. Being up-regulated, beta 3-AR plays a more important role in the regulation of cardiac function during heart failure. However, the effect of chronic blocking of beta 3-AR on heart failure has not been fully elucidated. In this study, we used a selective beta 3-AR antagonist SR59230A to treat a well defined heart failure rat model chronically, then evaluated its effect on cardiac function and investigated the mechanism. Male Wistar rats were chosen randomly as controls (n = 8). Isoproterenol induced heart failure rats were randomly divided into ISO group (n = 10) and SR group (n = 10). The ISO group received intraperitoneal injection of 1 ml saline twice a day; the SR group received intraperitoneal injection of SR59230A 85 nmol in 1 ml saline twice a day; and the control group received no treatment. The treatment was started 24 hours after the last isoproterenol injection and continued for 7 weeks. Then we measured the following indexes: the ratio of heart weight to body weight (HW/BW) and the ratio of left ventricular weight to body weight (LVW/BW), collagen volume fraction (CVF), left ventricular end diastolic dimension (LVEDd), left ventricular end systolic dimension (LVESd), ejection fraction (EF), fractional shortening (FS) and the ratio of E wave to A wave (E/A), the mRNA and protein expression of beta 3-AR and eNOS, and cGMP level in the heart. The ratios HW/BW and LVW/BW were significantly increased in the ISO group compared with the control group (P < 0.01), but they were limited in the SR group (P < 0.05 compared with the ISO group). CVF increased in the ISO group and the SR group (P < 0.01), but it was significantly attenuated in the SR group (P < 0.01). LVEDd, LVESd and E/A ratio were significantly increased in the ISO group compared with the control group (P < 0.01), while EF and FS were significantly decreased (P < 0.01). Compared with the ISO group, the SR group showed that LVEDd, LVESd and E/A ratio were significantly decreased (P < 0.01), whereas EF and FS were significantly increased (P < 0.01). beta(3)-AR and eNOS mRNA and protein in the ISO group were significantly increased when compared with the control group (P < 0.01). These increases were all attenuated in the SR group compared with the ISO group (P < 0.01). The level of cGMP in myocardial tissue was significantly increased in the ISO group compared with the control group (P < 0.01), whereas SR59230A treatment normalized this increment (P < 0.01). Chronic blocking of beta 3-AR could ameliorate cardiac function in heart failure rats and its mechanism involves inhibition of the negative inotropic effect and attenuation of cardiac remodeling.

Propranolol causes a paradoxical enhancement of cardiomyocyte foetal gene response to hypertrophic stimuli

Pathological cardiac hypertrophy is associated with the expression of a gene profile reminiscent of foetal development. The non selective beta-adrenoceptor antagonist propranolol is able to blunt cardiomyocyte hypertrophic response in pressure-overloaded hearts. It remains to be determined whether propranolol also attenuates the expression of hypertrophy-associated foetal genes. To address this question, the foetal gene programme, of which atrial natriuretic peptide (ANP), the beta-isoform of myosin heavy chain (beta-MHC), and the alpha-skeletal muscle isoform of actin (skACT) are classical members, was induced by thoracic aortic coarctation (TAC) in C57BL/6 mice, or by phenylephrine, a selective alpha(1)-adrenoceptor agonist, in cultured rat neonatal cardiomyocytes. In TAC mice, the left ventricular weight-to-body weight (LVW/BW) ratio increased by 35% after 2 weeks. Levels of ANP, beta-MHC and skACT mRNA in the left ventricles increased 2.2-fold, 2.0-fold and 12.1-fold, respectively, whereas alpha-MHC and SERCA mRNA levels decreased by approximately 50%. Although propranolol blunted cardiomyocyte growth, with approximately an 11% increase in the LVW/BW ratio, it enhanced the expression of ANP, beta-MHC and skACT genes (10.5-fold, 27.7-fold and 22.7-fold, respectively). Propranolol also enhanced phenylephrine-stimulated ANP and beta-MHC gene expression in cultured cardiomyocytes. Similar results were obtained with metoprolol, a selective beta(1)-adrenoceptor antagonist, but not with ICI 118551, a beta(2)-adrenoceptor antagonist. Propranolol enhances expression of the hypertrophy-associated foetal genes mainly via the beta(1)-adrenoceptor blockade. Our results also suggest that, in pressure-overloaded hearts, cardiomyocyte growth and foetal gene expression occur as independent processes.

Ameliorative Effect of Combination of Fenofibrate and Rosiglitazone in Pressure Overload-Induced Cardiac Hypertrophy in Rats

The present study has been designed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor (PPAR)α agonist, rosiglitazone, a PPARγ agonist and the combination of both fenofibrate and rosiglitazone in partial abdominal aortic constriction (PAAC)-induced pathological cardiac hypertrophy in rats. Rats were subjected to PAAC for 4 weeks to produce pathological cardiac hypertrophy. The fenofibrate (3 mg/kg day^–1, p.o.), rosiglitazone (3 mg/kg day^–1, p.o.) and the combination of both fenofibrate (3 mg/kg day^–1, p.o.) and rosiglitazone (3 mg/kg day^–1, p.o.) were administered 3 days before PAAC and continued for 4 weeks after PAAC. The development of cardiac hypertrophy was assessed in terms of measuring ratio of left ventricular (LV) weight to body weight (LVW/BW), LV wall thickness (LVWT), LV protein content and LV collagen content. Further, the collagen accumulation in left ventricle was analyzed using picrosirius red staining. Moreover, the cross-sectional area (CSA) of cardiomyocytes was assessed using hematoxylin and eosin staining and measured using a NIH Scion image analyzer. The PAAC produced cardiac hypertrophy by increasing LVW/BW, LVWT, LV protein content, LV collagen content and mean CSA of cardiomyocytes. However, treatment with fenofibrate and rosiglitazone either alone or in combination significantly attenuated PAAC-induced increase in LVW/BW, LVWT, LV protein content, LV collagen content and mean CSA of cardiomyocytes. The combination of fenofibrate and rosiglitazone was more effective in attenuating the PAAC-induced cardiac hypertrophy than either drug alone. Thus, it may be concluded that dual activation of PPARα and PPARγ may provide synergistic benefits in preventing the development of pathological cardiac hypertrophy.

Regulation of phospholamban and sarcoplasmic reticulum ca2+-atpase by atorvastatin: implication for cardiac hypertrophy

Abnormal intracellular Ca2+ homeostasis in the myocardium has been suggested as the cause of cardiac hypertrophy, and this process can be prevented by the HMG-CoA reductase inhibitors, statins. In the present study, the effect of atorvastatin on left ventricular hypertrophy was investigated, and then whether the underlying mechanism was related to a defect in intracellular Ca2+ homeostasis explored. Twelve spontaneously hypertensive rats (SHR), at 8 weeks old, were used in this study, and received either distilled water or atorvastatin for ten weeks, with age-matched normotensive Wistar-Kyoto rats (WKY) used as controls. RT-PCR and western blotting were used to detect the mRNA and protein expressions of phospholamban (PLB) and sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), respectively, and a colorimetric method used to examine the SERCA2a activity. Additionally, cardiac hypertrophic indices, such as the cardiosomatic ratio, left ventricular weight to body weight (LVW/BW) ratio and cardiomyocytes transverse diameter (TDM), together with the systolic blood pressure (SBP) and serum lipids levels were also examined. After ten weeks, significant decreases were observed in both the mRNA and protein expression levels of SERCA2a, as well as its activity, in the hypertrophied hearts of the SHR. The administration of atorvastatin to the same strains of rats effectively inhibited these decreases, and the above cardiac hypertrophic indices, as well as the SBP and serum lipids levels were significantly decreased. However, no significant changes in the expressions of PLB were observed in WKY, SHR and atorvastatin-treated SHR. These findings demonstrated that through regulation of the PLB and SERCA2a levels in the hearts of SHR, atorvastatin can prevent the cardiac hypertrophy caused due to pressure overload, which provides a relatively new insight into the mechanism of atorvastatin in the prevention of cardiac hypertrophy.

Involvement of endogenous ouabain-like compound in the cardiac hypertrophic process in vivo

The Na +/K +-ATPase inhibitor ouabain has been shown to trigger hypertrophic growth of cultured cardiomyocytes; however, the significance of endogenous ouabain-like compound (OLC) in the hypertrophic process in vivo is unknown. Here we characterized the involvement of OLC in left ventricular (LV) hypertrophy induced by norepinephrine (NE) and angiotensin II (Ang II) infusions in rats. Administration of NE (300 μg/kg/h) via subcutanously implanted osmotic minipumps for 72 h resulted in a significant increase in left ventricular weight to body weight (LVW/BW) ratio ( P < 0.001) and a substantial up-regulation of atrial natriuretic peptide (ANP) gene expression (13.2-fold, P < 0.001). NE infusion induced a transient increase in plasma OLC levels at 12 h ( P < 0.05), which returned to control levels by 72 h. Adrenalectomy markedly reduced both basal and NE-induced increase in plasma OLC levels. LVW/BW ratio was not modulated by adrenalectomy; however, ANP gene expression was blunted by 44% ( P < 0.01) and 47% ( P < 0.05) at 12 and 72 h, respectively. In agreement, adrenalectomy reduced up-regulation of ANP without affecting LV mass in rats infused with Ang II (33 μg/kg/h). Administration of exogenous ouabain (1 nM to 100 μM) for 24 h had no effect on ANP gene expression in cultured neonatal rat ventricular myocytes. However, the up-regulation of ANP mRNA levels induced by the α-adrenergic agonist phenylephrine (1 μM) was markedly enhanced by ouabain (100 μM) (5.6-fold vs. 9.6-fold, P < 0.01). These data show that OLC as an adrenal-derived factor may be required for the induction LV ANP gene expression during the hypertrophic process.

Differential Role of Rho-Kinase in Pathological and Physiological Cardiac Hypertrophy in Rats

The present study was undertaken to investigate the effect of fasudil, a specific Rho-kinase inhibitor, in pathological cardiac hypertrophy induced by partial abdominal aortic constriction (PAAC) for 4 weeks in comparison with physiological cardiac hypertrophy caused by chronic swimming training (CST) for 8 weeks in rats. Fasudil (15 and 30 mg/kg day^–1 p.o.) treatment was started 3 days before PAAC and CST, and was continued for 4 weeks in PAAC and 8 weeks in the CST experimental model. Left ventricular (LV) function and LV hypertrophy were assessed by measuring LVDP, +dp/dt_max, –dp/dt_max, ratio of LV weight to body weight (LVW/BW), LV wall thickness (LVWT), LV collagen content, protein content and RNA concentration. Further, venous pressure (VP) and mean arterial blood pressure (MABP) were recorded. Moreover, DNA gel electrophoresis was employed to assess myocardial cell death. PAAC but not CST produced LV dysfunction by decreasing LVDP, +dp/dt_max, –dp/dt_max and increasing LV collagen content. Further, PAAC and CST were noted to produce LV hypertrophy by increasing LVW/BW, LVWT, LV protein content and LV RNA concentration. Moreover, in contrast to CST, PAAC has significantly increased VP, MABP and LV necrotic cell death. Fasudil, a Rho-kinase inhibitor, markedly attenuated PAAC-induced LV dysfunction, LV hypertrophy, increase in VP, MABP and LV necrotic cell death. However, it did not modulate the CST-induced LV hypertrophy. These results have implicated Rho-kinase in PAAC-induced LV dysfunction and pathological cardiac hypertrophy. However, Rho-kinase may not be involved in CST-induced physiological cardiac hypertrophy.

Possible role of poly(ADP-ribose) polymerase in pathological and physiological cardiac hypertrophy

The present study was designed to investigate the effect of 5-aminoisoquinoline, a specific poly(ADP-ribose) polymerase (PARP) inhibitor, in partial abdominal aortic constriction (PAAC) for 4 weeks it induced pathological and chronic swimming training (CST) for 8 weeks it induced physiological cardiac hypertrophy. 5-Aminoisoquinoline (0.3 mg/kg/day and 3 mg/kg/day, i.p.) treatment was started 3 days before PAAC and CST, and it was continued for 4 weeks after PAAC and 8 weeks after initiation of CST. The left ventricular (LV) function and LV hypertrophy were assessed by measuring LVDP, dp/dtmax, dp/dtmin, ratio of LV weight to body weight (LVW/BW), LV wall thickness (LVWT), LV collagen content, LV protein content, and LV RNA concentration. Further, venous pressure (VP) and mean arterial blood pressure (MABP) were recorded. The PAAC, but not CST, produced LV dysfunction by decreasing LVDP, dp/dtmax, dp/dtmin, and increasing LV collagen content. Further, PAAC and CST were noted to produce LV hypertrophy by increasing LVW/BW, LVWT, LV protein content, and LV RNA concentration. Moreover, in contrast to CST, PAAC significantly increased VP and MABP. The 5-aminoisoquinoline, a potent selective inhibitor of PARP, significantly attenuated PAAC-induced LV dysfunction, LV hypertrophy, increase in VP and MABP. On the other hand, treatment with 5-aminoisoquinoline did not modulate CST-induced physiological cardiac hypertrophy. These results implicate PARP in PAAC-induced LV dysfunction and pathological cardiac hypertrophy. However, PARP may not be involved in CST-induced physiological cardiac hypertrophy.