Zhu H, McElwee-Witmer S, Perrone M, Clark K L, Zilberstein A
Department of Cardiovascular Biology, Rhone-Poulenc Rorer Research and Development, Collegeville, PA 19426, USA.
Cell Death Differ. 2000 Sep;7(9):773-84. doi: 10.1038/sj.cdd.4400721.
Previous studies have shown that alpha-adrenergic activation reduces myocardial damages caused by ischemia/reperfusion. However, the molecular mechanisms of how alpha-adrenergic activation protects the myocardium are not completely understood. The objective of this study was to test the hypothesis that alpha-adrenergic activation protects the myocardium by, at least in part, inhibiting apoptosis in cardiomyocytes. The current data has shown that apoptosis in neonatal rat cardiomyocytes, induced by 24 h treatment with hypoxia (95% N2 and 5% CO2) and serum deprivation, was inhibited by co-treatment with phenylephrine. Pre-treatment with phenylephrine for 24 h also protected cardiomyocytes against subsequent 24 h treatment with hypoxia and serum deprivation. Exposure of cardiomyocytes to phenylephrine for up to 9 days under normoxic conditions did not cause apoptosis. The phenylephrine-mediated cytoprotection was blocked by an alpha-adrenergic antagonist, phentolamine. beta-adrenergic activation with isoproterenol did not protect cardiomyocytes against hypoxia and serum deprivation-induced apoptosis. Under hypoxic conditions, phenylephrine prevented the down-regulation of Bcl-2 and Bcl-X mRNA/protein and induced hypertrophic growth. Phenylephrine-mediated protection was abrogated by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin and was mimicked by the caspase-9 peptidic inhibitor LEHD-fmk. These results suggest that alpha-adrenergic activation protects cardiomyocytes against hypoxia and serum deprivation-induced apoptosis through regulating the expression of mitochondrion-associated apoptosis regulatory genes, preventing activation of mitochondrial damage-induced apoptosis pathway (cytochrome C-caspase-9), and activating hypertrophic growth.
先前的研究表明，α-肾上腺素能激活可减轻缺血/再灌注引起的心肌损伤。然而，α-肾上腺素能激活保护心肌的分子机制尚未完全明确。本研究的目的是验证以下假说：α-肾上腺素能激活至少部分通过抑制心肌细胞凋亡来保护心肌。目前的数据表明，用苯肾上腺素共同处理可抑制新生大鼠心肌细胞因缺氧（95% N2和5% CO2）处理24小时及血清剥夺所诱导的凋亡。用苯肾上腺素预处理24小时也可保护心肌细胞免受随后24小时缺氧和血清剥夺处理的影响。在常氧条件下，将心肌细胞暴露于苯肾上腺素长达9天不会导致凋亡。α-肾上腺素能拮抗剂酚妥拉明可阻断苯肾上腺素介导的细胞保护作用。用异丙肾上腺素进行β-肾上腺素能激活不能保护心肌细胞免受缺氧和血清剥夺诱导的凋亡。在缺氧条件下，苯肾上腺素可防止Bcl-2和Bcl-X mRNA/蛋白的下调并诱导肥大生长。苯肾上腺素介导的保护作用被磷脂酰肌醇3-激酶（PI 3-激酶）抑制剂渥曼青霉素消除，并被半胱天冬酶-9肽抑制剂LEHD-fmk模拟。这些结果表明，α-肾上腺素能激活通过调节线粒体相关凋亡调节基因的表达、防止线粒体损伤诱导的凋亡途径（细胞色素C-半胱天冬酶-9）的激活以及激活肥大生长来保护心肌细胞免受缺氧和血清剥夺诱导的凋亡。
