Fortuño M A, Ravassa S, Etayo J C, Díez J
Vascular Pathophysiology Unit, School of Medicine, University of Navarra, Pamplona, Spain.
Hypertension. 1998 Aug;32(2):280-6. doi: 10.1161/01.hyp.32.2.280.
An association of increased apoptosis with overactivity of the local angiotensin-converting enzyme has been reported in cells from the left ventricle of adult rats with spontaneous hypertension (SHR). To gain insight into the regulation of cardiac apoptosis in arterial hypertension, we investigated the expression of the proteins Bcl-2 (an inhibitor of apoptosis) and Bax (an inducer of apoptosis) in the left ventricle of 30-week-old normotensive Wistar-Kyoto rats (WKY), SHR, and SHR treated with the angiotensin II type 1 receptor (AT1) antagonist losartan (20 mg x kg(-1) x d(-1)) during 14 weeks before death. The density of apoptotic cells was assessed by direct immunoperoxidase detection of biotin-labeled deoxyuridin nucleotides. The expression of Bcl-2 and Bax was assessed by Western blot analysis. Compared with WKY, untreated SHR exhibited increased (P<0.05) apoptosis, increased (P<0.01) Bax, and similar Bcl-2. The Bcl-2/Bax ratio (an inverse index of cell susceptibility to apoptosis) was lower (P<0.05) in untreated SHR than in WKY. The chronic administration of losartan was associated with the normalization of apoptosis, Bax expression, and the Bcl-2/Bax ratio in treated SHR. No changes in the expression of Bcl-2 were observed in these rats after treatment. No significant changes in the apoptotic density were observed between treated SHR with normal blood pressure and treated SHR with abnormally high blood pressure at the end of the treatment period. These results suggest that an association exists between increased apoptosis and overexpression of Bax oncoprotein in cells from the left ventricle of adult SHR. Chronic blockade of AT1 receptors prevents Bax overexpression and normalizes apoptosis in the left ventricle of SHR independently of its hemodynamic effect. On the basis of our findings, it can be proposed that the interaction of angiotensin II with its AT1 receptors may participate in the stimulation of Bax protein, which in turn renders cells from the left ventricle of SHR more susceptible to apoptosis.
据报道，在成年自发性高血压大鼠（SHR）左心室细胞中，凋亡增加与局部血管紧张素转换酶活性过高有关。为深入了解动脉高血压中心脏凋亡的调控机制，我们研究了30周龄正常血压的Wistar-Kyoto大鼠（WKY）、SHR以及在处死前14周用1型血管紧张素II受体（AT1）拮抗剂氯沙坦（20 mg·kg⁻¹·d⁻¹）治疗的SHR左心室中凋亡抑制蛋白Bcl-2和凋亡诱导蛋白Bax的表达。通过对生物素标记的脱氧尿苷核苷酸进行直接免疫过氧化物酶检测来评估凋亡细胞的密度。通过蛋白质印迹分析评估Bcl-2和Bax的表达。与WKY相比，未经治疗的SHR凋亡增加（P<0.05），Bax增加（P<0.01），而Bcl-2相似。未经治疗的SHR中Bcl-2/Bax比值（细胞对凋亡敏感性的反向指标）低于WKY（P<0.05）。氯沙坦的长期给药与治疗的SHR中凋亡、Bax表达以及Bcl-2/Bax比值的正常化有关。治疗后这些大鼠中未观察到Bcl-2表达的变化。在治疗期末，血压正常的治疗SHR与血压异常高的治疗SHR之间凋亡密度无显著变化。这些结果表明，成年SHR左心室细胞中凋亡增加与Bax癌蛋白的过度表达之间存在关联。AT1受体的慢性阻断可防止Bax过度表达，并使SHR左心室的凋亡正常化，而与血流动力学效应无关。根据我们的研究结果，可以推测血管紧张素II与其AT1受体的相互作用可能参与了Bax蛋白的刺激，这反过来使SHR左心室细胞更容易发生凋亡。
