Angiotensin II and tumour necrosis factor alpha as mediators of ATP-dependent potassium channel remodelling in post-infarction heart failure.
OBJECTIVE
Angiotensin II (Ang II) and tumour necrosis factor alpha (TNFalpha) 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.


RESULTS
We observed increased expression of both angiotensinogen and TNFalpha in the failing rat myocardium, with a regional gradient matching that of the K(ATP) subunit Kir6.1 expression. Both angiotensinogen and TNFalpha 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 TNFalpha. We observed increased Kir6.1 and SUR subunit and reduced Kir6.2 subunit mRNA expression in cardiomyocytes cultured with Ang II or TNFalpha, similar to what was observed in failing hearts. In patch-clamp experiments, cardiomyocytes cultured with Ang II or TNFalpha 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 TNFalpha expression, because TNFalpha-neutralizing antibody abolished the effect of Ang II, and in failing hearts, regional expression of angiotensinogen matched TNFalpha expression. Finally, Ang II and TNFalpha regulated K(ATP) subunit expression, possibly through differential expression of Forkhead box transcription factors.


CONCLUSIONS
This study identifies Ang II and TNFalpha as mediators of the remodelling of K(ATP) channels in heart failure.
Isidoro Tavares
Nadia
N
Division of Cardiology, Geneva University Hospitals, Geneva, Switzerland.
Philip-Couderc
Pierre
P
Baertschi
Alex J
AJ
Lerch
René
R
Montessuit
Christophe
C
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003981:Diazoxide / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism; D064233:Sulfonylurea Receptors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000804:Angiotensin II; D003981:Diazoxide; D051858:Forkhead Transcription Factors; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014409:Tumor Necrosis Factor-alpha; D000099161:Kcnj11 Channel; C092520:uK-ATP-1 potassium channel