科研之友
微信
新浪微博
Facebook
分享链接
摘要
Angiotensin II (Ang II) and tumour necrosis factor alpha (TNF alpha) are involved in the progression from compensated hypertrophy to heart failure. Here, we test their role in the remodelling of ATP-dependent potassium channel (K(ATP)) in heart failure, conferring increased metabolic and diazoxide sensitivity. We observed increased expression of both angiotensinogen and TNF alpha in the failing rat myocardium, with a regional gradient matching that of the K(ATP) subunit Kir6.1 expression. Both angiotensinogen and TNF alpha expression correlated positively with Kir6.1 and negatively with Kir6.2 expression across the post-infarction myocardium. To further identify a causal relationship, cardiomyocytes isolated from normal rat hearts were exposed in vitro to Ang II or TNF alpha. We observed increased Kir6.1 and SUR subunit and reduced Kir6.2 subunit mRNA expression in cardiomyocytes cultured with Ang II or TNF alpha, similar to what was observed in failing hearts. In patch-clamp experiments, cardiomyocytes cultured with Ang II or TNF alpha exhibited responsiveness to diazoxide, in terms of both K(ATP) current and action potential shortening. This was not observed in untreated cardiomyocytes and resembles the diazoxide sensitivity of failing cardiomyocytes that also overexpress Kir6.1. Ang II exerted its effect through induction of TNF alpha expression, because TNF alpha-neutralizing antibody abolished the effect of Ang II, and in failing hearts, regional expression of angiotensinogen matched TNF alpha expression. Finally, Ang II and TNF alpha regulated K(ATP) subunit expression, possibly through differential expression of Forkhead box transcription factors. This study identifies Ang II and TNF alpha as mediators of the remodelling of K(ATP) channels in heart failure.
- 出版日期2009-9-1
