Labpart-EA3852, Faculté de Médecine, Université François Rabelais, Tours, France.
Cardiovasc Res. 2011 Jul 15;91(2):320-9. doi: 10.1093/cvr/cvr072. Epub 2011 Mar 15.
Angiotensin II induces cardiac myocyte apoptosis and hypertrophy, which contribute to heart failure, possibly through enhanced oxidative stress. The aim of this work was to assess the impact of hemin (heme oxygenase-1 inducer) on NADPH oxidase activation, cardiac oxidative stress, and development of fibrosis in a rat model of renovascular hypertensive cardiomyopathy in comparison to an anti-hypertensive reference treatment with losartan.
A 3 week hemin treatment was tested in an angiotensin II-dependent hypertensive rat model and a cellular model of neonatal rat cardiomyocytes stimulated by angiotensin II. Our findings demonstrate that hemin prevented development of intercellular fibrosis, expression of collagen I, and disorganization of intracellular fibres. Oxidative stress and apoptosis evaluated in hypertensive myocardial tissue were decreased by hemin. The reference treatment with the angiotensin II receptor (AT(1)) antagonist (losartan) was less effective than hemin in prevention of fibrosis and oxidative stress, although it was more effective in reducing hypertension. Rac-1 activation and, subsequently, NADPH oxidase activity were further decreased with hemin than with losartan. Hemin enhanced the expression of phosphoinositide 3-kinase (PI3K) p85 regulatory subunit, in contrast to losartan. The PI3K/Akt signalling pathway activation by hemin was related to heme oxygenase-1 activation and an increase in biliverdin reductase, and its inhibition by LY294002 reversed the effects of hemin on collagen I and caspase-3 expression. Finally, hemin increased Akt activation, and concomitantly decreased RhoA and p38 mitogen-activated protein kinase activation.
We confirmed a positive effect of hemin on oxidative cardiac damage, apoptosis, and fibrosis induced by hypertension by modulating the NADPH oxidase activation through enhanced expression of the PI3K p85 regulatory subunit.
血管紧张素 II 可诱导心肌细胞凋亡和肥大，导致心力衰竭，其可能通过增强氧化应激来实现。本研究旨在评估血红素（血红素氧合酶-1 诱导剂）对血管紧张素 II 依赖性高血压性心肌病大鼠模型中 NADPH 氧化酶激活、心脏氧化应激和纤维化发展的影响，并与血管紧张素 II 受体（AT1）拮抗剂（氯沙坦）的抗高血压参考治疗进行比较。
在血管紧张素 II 依赖性高血压大鼠模型和血管紧张素 II 刺激的新生大鼠心肌细胞的细胞模型中，测试了 3 周血红素治疗。我们的研究结果表明，血红素可预防细胞间纤维化、I 型胶原表达和细胞内纤维结构紊乱的发展。血红素可降低高血压心肌组织中的氧化应激和凋亡。血管紧张素 II 受体（AT1）拮抗剂（氯沙坦）的参考治疗在预防纤维化和氧化应激方面的效果不如血红素，但在降低高血压方面的效果优于血红素。与氯沙坦相比，血红素进一步降低 Rac-1 激活和随后的 NADPH 氧化酶活性。血红素增强了磷酸肌醇 3-激酶（PI3K）p85 调节亚基的表达，而氯沙坦则相反。血红素对 PI3K/Akt 信号通路的激活与血红素氧合酶-1 的激活和胆红素还原酶的增加有关，其通过 LY294002 抑制逆转了血红素对胶原 I 和 caspase-3 表达的影响。最后，血红素增加了 Akt 的激活，同时降低了 RhoA 和 p38 丝裂原活化蛋白激酶的激活。
我们通过增强 PI3K p85 调节亚基的表达来调节 NADPH 氧化酶的激活，证实了血红素对高血压引起的心脏氧化损伤、凋亡和纤维化的积极作用。
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