Increased expression of calcium-sensing receptors in atherosclerosis confers hypersensitivity to acute myocardial infarction in rats
- 580 Downloads
Acute myocardial infarction (AMI) is a leading cause of death worldwide. Most cases of AMI result from coronary atherosclerosis (AS). The pathogenic mechanisms underlying AS lesions and AMI are incompletely understood. Calcium-sensing receptors (CaSR) belong to a family of G-protein-coupled receptors. We previously discovered that CaSR was expressed in the heart tissue of adult rats. CaSR may contribute to AMI in AS. We initially established a rat model of AS by injection of vitamin D3 and feeding with a high-fat diet. Isoproterenol (ISO) was used to induce AMI. The MB isoenzyme of creatine kinase (CK-MB), lactate dehydrogenase (LDH), cardiac troponin T (cTnT), tetrazolium chloride staining, and cardiac function parameters were selected as indicators of myocardial damage or necrosis. Cardiac apoptosis was analyzed by transferase dUTP nick-end labeling (TUNEL) assay. Expression of CaSR, Bcl-2, Bax, caspase-3, p-ERK1/2, p-JNK, and p-p38 were determined by Western blot analysis. Compared with the control group, levels of cTnT, CK-MB, and LDH; number of TUNEL-positive cells; and expression of CaSR, Bax, caspase-3, p-ERK1/2, p-JNK and p-p38, were significantly increased, whereas cardiac function and expression of Bcl-2 were decreased markedly in isoproterenol (ISO)-treated group (C/ISO) and AS groups. These changes were significant in the AS/ISO group than in the C/ISO group or AS group. The upregulation of CaSR during AS formation renders hypersensitivity to AMI. Activation of the pro-apoptotic mitochondria pathway and JNK-p38 MAPK pathway triggered by increased expression of CaSR may be one of molecular mechanisms underlying AMI in AS.
KeywordsAcute myocardial infarction (AMI) Atherosclerosis (AS) Apoptosis Calcium sensing receptors (CaSR)
This work was supported by the National Basic Research Program of China (973 Program, grant number 2007CB512000); National Natural Science Foundation of China (number 30871012,81000059 and 30700288); Youth Fund of Jiamusi University (number Sq2011-025).
- 3.Greaves DR, Häkkinen T, Lucas AD, Liddiard K, Jones E, Quinn CM, Senaratne J, Green FR, Tyson K, Boyle J, Shanahan C, Weissberg PL, Gordon S, Ylä-Hertualla S (2011) Linked chromosome 16q13 chemokines, macrophage-derived chemokine, fractalkine, and thymus and activation-regulated chemokine, are expressed in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol 21:923–929CrossRefGoogle Scholar
- 9.Wang LN, Wang C, Lin Y, Xi YH, Zhang WH, Zhao YJ, Li HZ, Tian Y, Lv YJ, Yang BF, Xu CQ (2008) Involvement of calcium-sensing receptor in cardiac hypertrophy-induced by angiotensin II through calcineurin pathway in cultured neonatal rat cardiomyocytes. Biochem Biophys Res Commun 369:584–589PubMedCrossRefGoogle Scholar
- 15.Rajadurai M, Prince PSM (2005) Comparative effects of Aegle marmelos extract and alpha-tocopherol on serum lipids, lipid peroxides and cardiac enzyme levels in rats with isoproterenol-induced myocardial infarction. Singap Med J Feb 46(2):78–81Google Scholar
- 20.Mithal A, Kifor O, Kifor I, Vassilev P, Butters R, Krapcho K, Simin R, Fuller F, Hebert SC, Brown EM (1995) The reduced responsiveness of cultured bovine parathyroid cells to extracellular Ca2+ is associated with marked reduction in the expression of extracellular Ca2+-sensing receptor messenger ribonucleic acid and protein. Endocrinology 136:3087–3092PubMedCrossRefGoogle Scholar
- 21.Sun YH, Zhang L, Xu CQ, Li H, Shi S, Zhao YJ, Han LP, Zhang HY (2006) Expression of calcium-sensing receptor in the rat cardiac tissue at different age and its relation with anoxia-reperfusion injury. Chin J Pathophysiol 22:1506–1509Google Scholar
- 27.Tanaka M, Mokhtari GK, Terry RD, Balsam LB, Lee KH, Kofidis T, Tsao PS, Robbins RC (2004) Overexpression of human copper/zinc superoxide dismutase (SOD1) suppresses ischemia-reperfusion injury and subsequent development of graft coronary artery disease in murine cardiac grafts. Circulation 110:II200–II206PubMedGoogle Scholar
- 29.Guo J, Li HZ, Zhang WH, Wang LC, Wang LN, Zhang L, Li GW, Li HX, Yang BF, Wu L, Wang R, Xu CQ (2010) Increased expression of calcium-sensing receptors induced by ox-LDL amplifies apoptosis of cardiomyocytes during simulated ischaemia/reperfusion. Clin Exp Pharmacol Physiol 37:e128–e135PubMedCrossRefGoogle Scholar
- 37.Yue TL, Wang C, Gu JL, Ma XL, Kumar S, Lee JC, Feuerstein GZ, Thomas H, Maleeff B, Ohlstein EH (2000) Inhibition of extracellular signal-regulated kinase enhances ischemia/reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart. Circ Res 86:692–699PubMedGoogle Scholar