calpain and Hypertrophy--Right-Ventricular

The calpain-1-activated apoptotic pathway plays a key role in right ventricular hypertrophy (RVH). Taurine has been shown to attenuate apoptosis by inhibiting calpain activity. This experiment aimed to determine whether taurine could prevent RVH by inhibiting the calpain-1/cytochrome c apoptotic pathway. The broilers were given 1% taurine dissolved in drinking water and were raised at 10 °C ~ 12 °C from day 21 to day 42. At 21 d, 28 d, 35 d and 42 d, the right ventricular (RV) tissues were collected. Increased RVH index, angiotensin II, norepinephrine and atrial natriuretic peptide mRNA expression were reduced by taurine in the broiler RVs. Taurine obviously inhibited cardiomyocyte apoptosis via maintaining the mitochondrial membrane potential and decreased the activation of caspase-9 and caspase-3 in the broiler RVs. The antioxidant assay demonstrated that taurine enhanced the activities of superoxide dismutase, total antioxidant capacity and glutathione peroxidase and the glutathione/glutathione disulfide ratio. Western blot results revealed that taurine also downregulated the expression of calpain-1 and cytosolic cytochrome c while upregulating the expression of Bcl-2/Bax and mitochondrial cytochrome c in broiler cardiomyocytes during RVH. In summary, we found that taurine could enhance cardiomyocyte antioxidant ability and further prevented cardiomyocyte apoptosis by inhibiting the calpain-1/cytochrome c pathway during RVH in broilers.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Calpain; Caspase 3; Caspase 9; Chickens; Cytochromes c; Hypertrophy, Right Ventricular; Metabolic Networks and Pathways; Myocytes, Cardiac; Taurine

To explore the role of calpain in pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension and the underlying mechanisms.
. Sprague-Dawley rats were randomly divided into the hypoxia group and the normoxia control group. Right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) were monitored by a method with right external jugular vein cannula. Right ventricular hypertrophy index was presented as the ratio of right ventricular weight to left ventricular weight (left ventricle plus septum weight). Levels of calpain-1, -2 and -4 mRNA in pulmonary artery were determined by real-time PCR. Levels of calpain-1, -2 and -4 protein were determined by Western blot. Primary rat pulmonary arterial smooth muscle cells (PASMCs) were divided into 4 groups: a normoxia control group, a normoxia+MDL28170 group, a hypoxia group and a hypoxia+MDL28170 group. Cell proliferation was detected by MTS and flow cytometry. Levels of Ki-67 and proliferating cell nuclear antigen (PCNA) mRNA were determined by real-time PCR.
. RVSP, mPAP and right ventricular remodeling index were significantly elevated in the hypoxia group compared to those in the normoxia group. In the hypoxia group, pulmonary vascular remodeling was significantly developed, accompanied by up-regulation of calpain-1, -2 and -4. MDL28170 significantly inhibited hypoxia-induced proliferation of PASMCs concomitant with the suppression of Ki-67 and PCNA mRNA expression.
. Calpain mediates vascular remodeling via promoting proliferation of PASMCs in hypoxia-induced pulmonary hypertension.. 目的：研究钙蛋白酶(calpain)在低氧诱导肺动脉高压肺血管重构中的作用及机制。方法：SD大鼠随机分为低氧模型组和常氧对照组。插管法测定大鼠右心室收缩压及平均肺动脉压，右心室/(左心室+室间隔)比值评价右心肥厚指数，HE染色检测血管重构情况，分别采用实时荧光定量PCR和Western印迹检测肺动脉calpain-1，-2和-4 mRNA和蛋白的表达。原代培养的大鼠肺动脉平滑肌细胞分为4组：常氧对照组、常氧对照+
MDL28170(calpain抑制剂)组、低氧模型组、低氧模型+MDL28170组。MTS及流式细胞术观察细胞增殖情况，实时荧光定量PCR检测Ki-67及增殖细胞核抗原(proliferating cell nuclear antigen，PCNA) mRNA表达情况。结果：与常氧对照组大鼠比较，低氧模型组大鼠右心室收缩压、平均肺动脉压及右心肥厚指数显著增加，肺动脉血管显著重构；同时，低氧模型组大鼠肺动脉中calpain-1，-2，-4 mRNA和蛋白表达也显著上调。与常氧对照组细胞比较，低氧模型组细胞显著增殖，MDL28170可显著抑制低氧诱导的肺动脉平滑肌细胞增殖，同时逆转低氧诱导的Ki-67和PCNA mRNA表达上调。结论：calpain介导低氧诱导的肺动脉高压肺血管重构，其机制可能与介导低氧诱导的肺动脉平滑肌细胞增殖有关。.

Topics: Animals; Calpain; Cell Proliferation; Dipeptides; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Ki-67 Antigen; Myocytes, Smooth Muscle; Proliferating Cell Nuclear Antigen; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Up-Regulation; Vascular Remodeling

Genetic depletion of the dystrophin-related glycoprotein (DRGP) complex causes cardiomyopathy in animals and humans. The present study was undertaken to explore the possible involvement of alterations in DRGP in the development of the right ventricular failure in monocrotaline-administered rats (MCT rats). At the 6th and 8th weeks after subcutaneous administration of 60 mg/kg monocrotaline, echocardiographic examination showed that cardiac output indices were decreased and that the right ventricular Tei indices were increased, suggesting that right ventricular failure occurs, at the latest, by 6 weeks after monocrotaline-administration. The levels of alpha- and beta-sarcoglycan and beta-dystroglycan in the right ventricle of the MCT rats at the 6th and 8th weeks were markedly decreased, and these decreases were inversely related to the increase in the right ventricular Tei index of the MCT-administered animals. The content and activity of the Ca(2+)-activated neutral protease m-calpain in the right ventricle of the MCT rats were increased at the 4th to 8th weeks and those of matrix metalloproteinase-2, at the 6th and 8th weeks. These results suggest that m-calpain- and/or matrix metalloproteinase-2-mediated alterations in the contents of alpha-sarcoglycan, beta-sarcoglycan, and beta-dystroglycan may be involved in the development of right ventricular failure in MCT rats.

Topics: Animals; Calpain; Dystroglycans; Dystrophin-Associated Protein Complex; Heart Failure; Heart Ventricles; Hemodynamics; Hypertrophy, Right Ventricular; Male; Matrix Metalloproteinase 2; Monocrotaline; Myocardium; Rats; Rats, Wistar; Sarcoglycans; Time Factors; Ventricular Dysfunction, Right