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Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 21, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp162
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Angiotensin II and TNF{alpha} as mediators of ATP-dependent potassium channel remodeling in post-infarction heart failure

Nadia Isidoro Tavares1,2, Pierre Philip-Couderc3, Alex J. Baertschi3, René Lerch1,2 and Christophe Montessuit1,2

1 Geneva University Hospitals, Division of Cardiology, Geneva, Switzerland
2 Foundation for Medical Research, University of Geneva, Geneva, Switzerland
3 Department of Neurosciences, University of Geneva School of Medicine, Geneva, Switzerland

Corresponding author: Christophe Montessuit, PhD, Foundation for Medical Research, Cardiology 64 avenue de la Roseraie, 1211 Geneva 4, Switzerland. Phone: +41 22 37 27 216; Fax: +41 22 38 27 245. E-mail: christophe.montessuit{at}unige.ch

Aims: Angiotensin II (Ang II) and tumor necrosis factor {alpha} (TNF{alpha}) are involved in the progression from compensated hypertrophy to heart failure. Here we test their role in the remodeling of ATP-dependent potassium channel (KATP) in heart failure, conferring increased metabolic and diazoxide sensitivity.

Methods and Results: We observed increased expression of both angiotensinogen and TNF{alpha} in the failing rat myocardium, with a regional gradient matching that of the KATP 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 KATP 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 KATP subunit expression, possibly through differential expression of Forkhead box transcription factors.

Conclusions: This study identifies Ang II and TNF{alpha} as mediators of the remodeling of KATP channels in heart failure.

Time for primary review: 28 Days


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