Wistar大鼠心脏自发性病变的病理学观察

目的了解Wistar大鼠心脏自发性病变发病情况,为长期致癌性研究、老年病学研究及毒性病理学提供背景资料。方法采用160只清洁级Wistar大鼠,雌雄各半,常规饲养,分别在9月龄、12月龄、18月龄、24月龄时处死40只大鼠,HE及Masson三色法染色,观察心脏的病理改变。结果 9月龄Wistar大鼠心脏未见明显病理改变;12月龄Wistar大鼠月龄心脏病变的发病率为2.5%（1/40）,表现为少数心肌细胞变性坏死伴少量以单核细胞为主的炎细胞浸润;18月龄大鼠心脏病变的发病率为57.5%（23/40）,表现为轻至中度心肌病,雄性发病率高于雌性。24月龄大鼠100%（40/40）出现不同程度的心肌病,并有2.5%（1/40）发生心内膜下纤维组织增生。Masson染色显示9月龄大鼠心脏血管周围及心脏瓣膜环下有少量胶原纤维,随年龄增长,血管周围及心脏瓣膜环下胶原纤维逐渐增多,并延伸入心肌细胞间。结论随年龄增长,大鼠心脏自发病变比率升高,主要病变为心肌病,偶尔可发生心内膜下纤维组织增生;胶原纤维沉积首先发生于血管周围及心脏瓣膜环下,随年龄增长而增多,可能与大鼠心肌病的的发生密切相关。     

黄芪注射液对缺血性心肌病大鼠心肌自噬及心肌重塑的影响

目的:研究黄芪注射液对缺血性心肌病大鼠心肌重塑、网腔钙结合蛋白(calumenin)及自噬影响。方法:36只雄性SD大鼠分为正常对照组(n=12)、缺血性心肌病组(n=12)、黄芪注射液组(n=12),3组大鼠术前行心电图及心脏彩超检查后,正常对照组不做任何处理,而缺血性心肌病组和黄芪注射液组大鼠开胸结扎冠状动脉20 min后,解开结扎线行再灌注后关闭胸腔建立心肌缺血模型,黄芪注射液组术后每次注射黄芪注射液10 g/kg体重,每周注射1次,共注射4次。3组大鼠术后4周行心脏彩超检查后处死大鼠取心脏行HE染色、VG染色,观察心肌病理改变,用Western blot技术检测各组大鼠心肌细胞calumenin、LC3-Ⅰ、LC3-Ⅱ表达变化及LC3-Ⅰ/LC3-Ⅱ比值变化。结果:与缺血性心肌病组比较,黄芪注射液组大鼠心脏彩超及心肌病理得到明显改善;同时,calumenin表达增加LC3-Ⅰ/LC3-Ⅱ比值表达降低(P<0.01)。结论:黄芪注射液对缺血性心肌病大鼠心室重塑及心肌细胞自噬有明显抑制作用,该作用可能是通过calumenin所介导的。     

缺血性心肌病大鼠心肌细胞自噬在心肌重塑中的作用*

目的:研究缺血性心肌病大鼠心肌细胞自噬在心肌重塑中的作用。方法:36 只雄性SD大鼠分为正常对照组、假手术组、缺血性心肌病组( n=12),3组大鼠术前行心脏彩超检查,正常对照组大鼠不进行处理;假手术组大鼠开胸后不结扎冠状动脉,关闭胸腔;缺血性心肌病组大鼠开胸结扎冠状动脉20 min后,解开结扎线行再灌注后关闭胸腔,3组大鼠术后4周行心脏彩超检查后处死大鼠取心脏行HE染色、masson染色,观察心肌病理改变,用Western blot技术检测各组大鼠心肌细胞GRP78、LC3-I、LC3-II、Beclin-I表达及LC3-II/LC3-I比值的变化。结果:与正常组及假手术组比较,缺血性心肌病大鼠心室扩大,EF值降低;心肌排列紊乱,心肌纤维化增加;线粒体空泡化严重;内质网应激关键蛋白GRP78上调;自噬相关蛋白LC3-I、LC3-II、Beclin-I及LC3-II/LC3-I比值增加。结论:缺血性心肌病大鼠心肌细胞中内质网应激和自噬可能在心肌重塑中具有重要作用。     

Beneficial effect of ACE inhibitor in congestive heart failure

The effects of captopril, an angiotensin-converting enzyme inhibitor, on congestive heart failure (CHF) were investigated in animal and clinical studies. Congestive heart failure was induced in rats by a combination of pressure and volume overload. Cardiac pressure overload was induced by constricting one renal artery (Goldblatt rat) and volume overload was induced by aorto-caval fistula. Captopril (100 mg/kg/day) was then administered for 14 weeks. Isometric contraction was assessed using isolated left ventricular papillary muscles. The maximum developed tension and the maximum rate of increase in tension (dT/dtmax) were decreased in untreated rats with CHF and improved in captopriltreated rats. The left ventricular myosin isoenzyme pattern was shifted towards V3 in untreated rats with CHF, and was shifted back towards V1 in the captopril-treated rats. In the clinical study, captopril (37.5–75 mg/day) was administered to patients with cardiomyopathy for 12 months. There was no effect on left ventricular mass in hypertrophic cardiomyopathy, although systolic anterior motion of the mitral valve disappeared in one patient. In dilated cardiomyopathy, however, left ventricular mass tended to decrease. These results indicate that captopril has a beneficial effect in congestive heart failure.     

Role of changes in cardiac metabolism in development of diabetic cardiomyopathy

In patients with diabetes, an increased risk of symptomatic heart failure usually develops in the presence of hypertension or ischemic heart disease. However, a predisposition to heart failure might also reflect the effects of underlying abnormalities in diastolic function that can occur in asymptomatic patients with diabetes alone (termed diabetic cardiomyopathy). Evidence of cardiomyopathy has also been demonstrated in animal models of both Type 1 (streptozotocin-induced diabetes) and Type 2 diabetes (Zucker diabetic fatty rats and ob/ob or db/db mice). During insulin resistance or diabetes, the heart rapidly modifies its energy metabolism, resulting in augmented fatty acid and decreased glucose consumption. Accumulating evidence suggests that this alteration of cardiac metabolism plays an important role in the development of cardiomyopathy. Hence, a better understanding of this dysregulation in cardiac substrate utilization during insulin resistance and diabetes could provide information as to potential targets for the treatment of cardiomyopathy. This review is focused on evaluating the acute and chronic regulation and dysregulation of cardiac metabolism in normal and insulin-resistant/diabetic hearts and how these changes could contribute toward the development of cardiomyopathy.     

Sorbitol accumulation in heart: implication for diabetic cardiomyopathy

Sorbitol levels in heart were determined in streptozotocin-induced diabetic rats. Significantly higher levels were found in hearts of diabetic rats compared to normal rats. The findings are compatible with either significantly higher de novo synthesis of sorbitol in heart than is generally believed or uptake of circulating sorbitol by heart as previously indicated by nuclear magnetic resonance (NMR) in vivo metabolic imaging. Sorbitol accumulation in heart tissue may play a role in the pathogenesis of diabetic cardiomyopathy as has been implicated in cataract formation.     

Doxorubicin Inactivates Myocardial Cytochrome c Oxidase in Rats: Cardioprotection by Mito-Q

Doxorubicin (DOX) is used for treating various cancers. Its clinical use is, however, limited by its dose-limiting cardiomyopathy. The exact mechanism of DOX-induced cardiomyopathy still remains unknown. The goals were to investigate the molecular mechanism of DOX-induced cardiomyopathy and cardioprotection by mitoquinone (Mito-Q), a triphenylphosphonium-conjugated analog of coenzyme Q, using a rat model. Rats were treated with DOX, Mito-Q, and DOX plus Mito-Q for 12 weeks. The left ventricular function as measured by two-dimensional echocardiography decreased in DOX-treated rats but was preserved during Mito-Q plus DOX treatment. Using low-temperature ex vivo electron paramagnetic resonance (EPR), a time-dependent decrease in heme signal was detected in heart tissues isolated from rats administered with a cumulative dose of DOX. DOX attenuated the EPR signals characteristic of the exchange interaction between cytochrome c oxidase (CcO)-Fe(III) heme a₃ and Cu_B. DOX and Mito-Q together restored these EPR signals and the CcO activity in heart tissues. DOX strongly downregulated the stable expression of the CcO subunits II and Va and had a slight inhibitory effect on CcO subunit I gene expression. Mito-Q restored CcO subunit II and Va expressions in DOX-treated rats. These results suggest a novel cardioprotection mechanism by Mito-Q during DOX-induced cardiomyopathy involving CcO.     

Nox4-derived reactive oxygen species mediate cardiomyocyte injury in early type 1 diabetes

Oxidative stress contributes to diabetic cardiomyopathy. This study explored the role of the NADPH oxidase Nox4 as a source of reactive oxygen species (ROS) involved in the development of diabetic cardiomyopathy. Phosphorothioated antisense (AS) or sense (S) oligonucleotides for Nox4 were administered for 2 wk to rats made diabetic by streptozotocin. NADPH oxidase activity, ROS generation, and the expression of Nox4, but Nox1 or Nox2, were increased in left ventricular tissue of the diabetic rats. Expression of molecular markers of hypertrophy and myofibrosis including fibronectin, collagen, α-smooth muscle actin, and β-myosin heavy chain were also increased. These parameters were attenuated by the administration of AS but not S Nox4. Moreover, the impairment of contractility observed in diabetic rats was prevented in AS- but not S-treated animals. Exposure of cultured cardiac myocytes to 25 mM glucose [high glucose (HG)] increased NADPH oxidase activity, the expression of Nox4, and molecular markers of cardiac injury. These effects of HG were prevented in cells infected with adenoviral vector containing a dominant negative form of Nox4. This study provides strong evidence that Nox4 is an important source of ROS in the left ventricle and that Nox4-derived ROS contribute to cardiomyopathy at early stages of type 1 diabetes.     

活血化瘀方抗糖尿病心肌病的药理调控机制研究

目的:从基因表达谱的角度探究活血化瘀方抗糖尿病心肌病的药理调控机制。方法:采用链脲霉素建立糖尿病心肌病大鼠模型后,随机分组并对其中一组给予活血化瘀方灌胃,检测生理数据,并取样进行基因表达水平检测。针对芯片数据,初处理后依次进行:基因表达差异分析、基因表达与性状相关性分析、基因连接性差异分析和加权的基因共表达网络分析,最后整合上述多种分析结果,寻找关键基因。结果:成功建立糖尿病心肌病大鼠模型,并得到一系列从不同角度分析的结果:一千多个差异表达基因,五千多个差异连接性基因,鉴定出三个共表达网络中的关键模块以及三个关键基因。结论:活血化瘀方通过调节与糖尿病心肌病或者糖尿病密切相关的生物分子及其活动,同时综合作用于多种基础的细胞生理活动,从而影响糖尿病心肌病的发展。     

阿托伐他汀通过RGS6改善糖尿病心肌病大鼠心功能的作用及其机制研究

目的:探讨阿托伐他汀通过调节RGS6/NAD(P)H氧化酶/活性氧生成通路保护糖尿病心肌病大鼠心功能的药理作用机制。方法:40只6周龄雄性Wistar大鼠按随机数字表法随机分为对照组,糖尿病心肌病模型组,低剂量阿托伐他汀组,高剂量阿托伐他汀组,每组10只。实验过程中动态监测大鼠体质量及血脂水平;实验结束后脉冲多普勒检测各组大鼠心功能指标;组织活性氧检测试剂盒检测心肌组织中活性氧的水平;免疫组化法检测大鼠心肌组织中RGS6的表达;Western blot法检测大鼠心肌组织中RGS6及NAD (P)H氧化酶活性亚单位p47phox和p67phox的水平。结果:与对照组相比,糖尿病心肌病模型大鼠体质量明显减少(P0.01),血脂水平明显升高(P0.01),心脏E/A、LVEF、FS值降低(P0.01),心肌组织活性氧生成明显增多(P0.01),心肌组织RGS6及p47phox、p67phox表达明显上调(P0.01),而不同剂量阿托伐他汀干预均可有效逆转上述指标的改变。结论:阿托伐他汀对糖尿病心肌病大鼠的心脏具有明显保护作用,其机制可能与对RGS6/NAD(P)H氧化酶/活性氧生成通路的抑制有关。     

Chymase inhibition reduces the progression to heart failure after autoimmune myocarditis in rats

Chymase has been known as a local angiotensin II-generating enzyme in the cardiovascular system in dogs, monkeys, hamsters, and humans; however, recently it was reported that chymase also has various other functions. Therefore, we decided to examine whether the inhibition of chymase improves disease conditions associated with the pathophysiology of dilated cardiomyopathy in rats and its possible mechanism of action as rat chymase is unable to produce angiotensin II. We examined the effect of TY-51469, a novel chymase inhibitor (0.1 mg/kg/day [group CYI-0.1, n = 15] and 1 mg/kg/day [group CYI-1, n = 15]), in myosin-immunized postmyocarditis rats. Another group of myosin-immunized rats was treated with vehicle (group V, n = 15). Age-matched normal rats without immunization (group N, n = 10) were also included in the study. After 4 weeks of treatment, we evaluated cardiac function; area of fibrosis; fibrogenesis; levels of transforming growth factor (TGF)-beta1 and collagen III; hypertrophy and its marker, atrial natriuretic peptide (ANP); and mast cell activity. Survival rate and myocardial functions improved dose-dependently with chymase inhibitor treatment after myosin immunization. A reduction in the percent area of myocardial fibrosis, fibrogenesis, myocardial hypertrophy, and mast cell activity along with a reduction in TGF-beta1, collagen III, and ANP levels in the myocardium were noted in postmyocarditis rats that received chymase inhibitor treatment. The treatment also decreased myocardial aldosterone synthase levels in those animals. Inhibition of chymase reduces the pathogenesis of postmyocarditis dilated cardiomyopathy and progression to heart failure by preventing the pathological remodeling and residual inflammation in rats.     

Increased expression of integrin-linked kinase improves cardiac function and decreases mortality in dilated cardiomyopathy model of rats

Aims

Integrin-linked kinase (ILK) is a multifunctional kinase linking the extracellular matrix to intracellular signaling pathways, whose activation in the heart gives rise to a number of functional consequences. The aim of this study is to demonstrate the therapeutic and survival benefit of cardiac ILK overexpression in a rat model of dilated cardiomyopathy.

Methods and Results

The dilated cardiomyopathy model was generated in rats by intraperitoneal administration of six equal doses of doxorubicin over a 2 week period. Five weeks after the first injection, echocardiographic analysis demonstrated impaired cardiac function and, at that point, recombinant adenoviral vector harboring ILK cDNA or vehicle was injected into the myocardium, and the rats re-studied 4 weeks later. Compared with vehicle injection, ILK treatment ameliorated inflammatory cell infiltration and cardiomyocyte degeneration, as well as left ventricular dilation and dysfunction. ILK treatment was also associated with a reduction in apoptosis and an increase in proliferation of cardiomyocytes, as well as decreased oxidative stress and autophagic vacuole accumulation. Importantly, mortality was lower in rats following ILK treatment than in those following vehicle injection. In cultured neonatal rat cardiomyocytes, we also found that ILK overexpression protected against doxorubicin-induced apoptosis, giving rise to an increase in their proliferation.

Conclusions

These data demonstrate for the first time that ILK gene therapy improves cardiac function and survival in a model of dilated cardiomyopathy, and this may be mediated through suppression of inflammation, prevention of ventricular remodeling, inhibition of cardiomyocyte apoptosis and autophagy, and stimulation of cardiomyocyte proliferation.     

Defective intracellular Ca(2+) signaling contributes to cardiomyopathy in Type 1 diabetic rats

The goal of the study was to determine whether defects in intracellular Ca(2+) signaling contribute to cardiomyopathy in streptozotocin (STZ)-induced diabetic rats. Depression in cardiac systolic and diastolic function was traced from live diabetic rats to isolated individual myocytes. The depression in contraction and relaxation in myocytes was found in parallel with depression in the rise and decline of intracellular free Ca(2+) concentration ([Ca(2+)](i)). The sarcoplasmic reticulum (SR) Ca(2+) store and rates of Ca(2+) release and resequestration into SR were depressed in diabetic rat myocytes. The rate of Ca(2+) efflux via sarcolemmal Na(+)/Ca(2+) exchanger was also depressed. However, there was no change in the voltage-dependent L-type Ca(2+) channel current that triggers Ca(2+) release from the SR. The depression in SR function was associated with decreased SR Ca(2+)-ATPase and ryanodine receptor proteins and increased total and nonphosphorylated phospholamban proteins. The depression of Na(+)/Ca(2+) exchanger activity was associated with a decrease in its protein level. Thus it is concluded that defects in intracellular Ca(2+) signaling caused by alteration of expression and function of the proteins that regulate [Ca(2+)](i) contribute to cardiomyopathy in STZ-induced diabetic rats. The increase in phospholamban, decrease in Na(+)/Ca(2+) exchanger, and unchanged L-type Ca(2+) channel activity in this model of diabetic cardiomyopathy are distinct from other types of cardiomyopathy.     

Neutralization of pathogenic beta1-receptor autoantibodies by aptamers in vivo: the first successful proof of principle in spontaneously hypertensive rats

Autoantibodies (AABs) against the second extracellular loop of the beta1-receptor (beta1(II)-AABs) are found as a pathogenic driver in patients with idiopathic dilated cardiomyopathy, Chagas cardiomyopathy, peripartum cardiomyopathy, and myocarditis, and have been increasingly seen as a treatment target. We recently identified an aptamer (single short DNA strand) that specifically binds and neutralizes beta1(II)-AABs. Via application of this aptamer, a new treatment strategy for diseases associated with the cardio-pathogenic beta1(II)-AABs could be developed. Spontaneously hypertensive rats (SHR) positive for beta1(II)-AABs were treated five times at weekly intervals (bolus application of 2 mg/kg body weight followed by an infusion of the same amount over 20 min). SHR responded to aptamer treatment with a strong reduction in the cardio-pathogenic beta1(II)-AABs. The AABs did not substantially return within the study period. No signs for aptamer toxicity were observed by visual examination of the heart, liver, and kidney, or by measurement of plasma CK, ALT, and creatinine. The aptamer’s potential for beta1(II)-AAB neutralization and consequently for cardiomyopathy treatment has been shown for the first time in vivo.     

Decreased RhoA expression in myocardium of diabetic rats

Diabetic cardiomyopathy is 1 of the major causes of death in diabetic patients, but the pathogenesis is unclear. There is evidence that RhoA, a small GTPase, might be involved in cardiac function. This study, therefore, analyzed RhoA expression and activation in hearts of diabetic rats. Male Sprague-Dawley rats were divided into control and diabetic groups of 18 each. Diabetes was induced by intravenous injection of streptozotocin (55 mg/kg). Rats were studied 3 weeks after induction of diabetes. Heart rate, which was measured 24 h/day, decreased by 93 +/- 7 beats/min in diabetic rats. There was a 62% decrease (p < 0.01) in RhoA mRNA expression in heart tissues (left ventricle) of diabetic rats (38.5 +/- 6.7 x 106 molecules/microg total RNA) compared with controls (101 +/- 10.3 x 106 molecules/microg total RNA). Western blot showed a 33% decrease in total RhoA protein expression in heart tissues of diabetic rats compared with controls (p < 0.05). A reduced RhoA translocation in heart tissues of diabetic rats was determined by a 64% decrease in membrane-bound RhoA (p < 0.01 vs. control group), indicating that the activation of RhoA is markedly reduced in diabetic myocardium. Our data suggest that down-regulated RhoA may be involved in cardiomyopathy in diabetic rats.     

On the potential use of echocardiography for assessing the formation of alcoholic cardiomyopathy

Chronic alcohol abuse not only leads to significant human psychic and social degradation, but also promotes the formation of alcoholic cardiomyopathy, which is one of the leading causes of high mortality of alcoholics. However, to date, there are no unified approaches in the prevention and treatment of alcoholic cardiomyopathy in clinics, primarily due to the lack of an adequate model in experimental pharmacology that could assess the stages of the formation of alcoholic cardiomyopathy objectively in real time, and thereby create the basis for the search and study of the mechanisms of action of drugs for the treatment of this serious disease. Studying the possibility of the use of echocardiography in experiments on rats with prolonged forced alcoholism is one of the approaches to solve this problem. It was shown that significant changes in intracardiac echocardiography hemodynamics corresponding to that known from the clinics begin to form from the 20th week of systematic consumption of alcohol by rats. By this time, the reduction in inotropic function of the heart in alcoholized rats compared to control rats is observed: the shortening fraction (SF) is 41.9% (40.3–42.2) and 51.3% (48.8–59.1), respectively, and the ejection fraction (EF) is 78.8% (77.4–79.2) and 87.5% (84.6–92.4), respectively, p ≈ 0.0215. The dilated heart failure develops in rats from the 24th week of regular alcohol consumption, as illustrated not only by the dynamic reduction of SF and EF, but also by the dilatation of the heart. For example, the end-systolic dimension of the left ventricle in animals consuming alcohol compared with the control rats more than doubled (4.31 mm (3.80–4.41) and 2.0 mm (1.85–2.36), p ≈ 0.0008, and the end-diastolic dimension was 5.95 mm (5.13–6.37) and 4.52 mm (3.85–4.90), respectively; p ≈ 0.0171. Thus, the echocardiographic picture characteristic of alcoholic dilated cardiomyopathy is formed by the end of the 24th week of chronic alcoholization.     

蒙药新Ⅱ号对扩张型心肌病大鼠心功能、心肌细胞内质网应激及凋亡的作用

目的：探讨蒙药新Ⅱ号对阿霉素性扩张型心肌病大鼠心功能、心肌病理、心肌细胞内质网应激及凋亡作用。方法：30 只SD 雄性大鼠分为3组（n=10）： 正常对照组、模型组（腹腔注射阿霉素2 mg/kg体重,1次/周,用药4周后观察4周）和蒙药新Ⅱ号组（腹腔注射阿霉素2 mg/kg体重,1次/周,用药4周后,给予蒙药新Ⅱ号30 mg/kg·d灌胃,共4周）。观察大鼠的一般情况,8 周后行高频超声心动图检查,测定各项心功能指标,检查结束后处死大鼠,取心脏,行HE 染色、VG染色及电镜观察。用TUNEL 法检测各组大鼠心肌细胞凋亡, Western blot 检测各组大鼠心肌细胞内质网伴侣蛋白GRP78、GRP94及促凋亡因子CHOP、caspase-3表达。结果：与模型组相比较,①蒙药新Ⅱ号组大鼠心脏左室结构及血流动力学各项指标均有明显改善（P<0.05）。②蒙药新Ⅱ号组大鼠心肌病理积分明显下降（P<0.01）。③蒙药新Ⅱ号组大鼠心肌细胞内质网应激伴侣蛋白GRP78、GRP94、CHOP、caspase-3表达及细胞凋亡明显减少 （P<0.01）。结论：蒙药新Ⅱ号可改善扩张型心肌病大鼠心脏功能,减轻心肌病理变化,缓解内质网应激,减少心肌细胞凋亡。这一实验结果可能是蒙药新Ⅱ号治疗扩张型心肌病作用机制之一。     

Involvement of 1,2-diacylglycerol in improvement of heart function by etomoxir in diabetic rats

Abnormal lipid metabolism has been proposed to be involved in the pathogenesis of diabetic cardiomyopathy. In this study, we measured myocardial lipid levels, including 1,2-diacylglycerol (1,2-DAG) and ceramide (CM), and myocardial function in diabetic rats. We also evaluated the effects of etomoxir (ETM), a carnitine palmitoyl transferase I inhibitor, on diabetic rat hearts from the viewpoints of alterations in lipid second messengers and myocardial function. Rats were injected with streptozotocin (60 mg/kg) to induce diabetes and were treated 5 weeks later with ETM (18 mg/kg) for 8 days. In diabetic rats, heart rate, systolic blood pressure, and fractional shortening were significantly reduced compared with those in controls. Treatment of diabetic rats with ETM ameliorated myocardial dysfunction other than heart rate. Myocardial 1,2-DAG levels in diabetic rats were significantly elevated compared with those in controls, while myocardial CM levels were not. ETM treatment caused an additional increase in myocardial 1,2-DAG levels in diabetic rats, but the CM levels did not change. There was a marked difference in fatty acid pattern of 1,2-DAG between diabetic and ETM-treated diabetic rat hearts. The fatty acids 18:1 and 18:2 were significantly increased and the fatty acids 16:0, 18:0, 20:4, and 22:6 were significantly reduced in ETM-treated diabetic rat hearts. These data suggest 1,2-DAG is involved in ameliorating myocardial dysfunction in diabetic rats and that its source is different between diabetic and ETM-treated diabetic rats. CM is unlikely to be involved in the pathogenesis of diabetic cardiomyopathy or the improvement of cardiac contractility in diabetic rats by ETM.     

Anti-apoptotic potential of gymnemic acid phospholipid complex pretreatment in Wistar rats with experimental cardiomyopathy

Cardiomyocyte apoptosis in heart failure has been the topic of research in many recent studies. In the present investigation, the potential cardioprotective effect of gymnemic acid phospholipid complex (GPC) on myocardial apoptosis and cardiac function was studied in doxorubicin (DOX; 30 mg/kg/ip/single dose)-induced cardiomyopathy model in rats. Doxorubicin induced cardiomyopathy was evidenced by significant hemodynamic changes (increased systolic, diastolic, mean arterial pressure and heart rate), decreased heart weight to body weight ratio, increase in serum lactate dehydrogenase (LDH) and Ca2+ levels and decrease in myocardial Na+/K+ ATPase levels along with caspase-3 activation. A marked reduction in glutathione, glutathione peroxidase, glutathione reductase, glutathione-S-transferase, superoxide dismutase and catalase levels along with increase in the levels of thiobarbituric acids (TBARS) were also observed in rat myocardium. In addition, DNA laddering observed on agarose gel electrophoresis and cardiac histopathology study further supplemented myocardial apoptosis. Pre-treatment with GPC significantly reduced DOX-induced cardiac toxicity, including improvement of hemodynamic variables and heart weight to body weight ratio, decreased serum Ca2+ level and LDH levels, myocardial caspase-3 levels, increased Na+/K+ ATPase levels and decreased myocardial TBARS levels and elevated antioxidant enzymes as compared to pathogenic control group. Further, the anti-apoptotic effect of GPC was verified by prevention of internucleosomal DNA laddering on agarose gel electrophoresis and attenuation of histopathological perturbations by doxorubicin. These observations demonstrate that GPC might serve as a cardioprotective formulation in DOX-induced cardiomyopathy in rats.