Cellular remodeling in heart failure disrupts K(ATP) channel-dependent stress tolerance. EMBO J 2003 Apr 15;22(8):1732-42
Date
04/19/2003Pubmed ID
12682006Pubmed Central ID
PMC154482DOI
10.1093/emboj/cdg192Scopus ID
2-s2.0-0037446942 (requires institutional sign-in at Scopus site) 82 CitationsAbstract
ATP-sensitive potassium (K(ATP)) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on K(ATP) channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor alpha induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, K(ATP) channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, K(ATP) channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by K(ATP) channel openers. Thus, disease-induced K(ATP) channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy.
Author List
Hodgson DM, Zingman LV, Kane GC, Perez-Terzic C, Bienengraeber M, Ozcan C, Gumina RJ, Pucar D, O'Coclain F, Mann DL, Alekseev AE, Terzic AMESH terms used to index this publication - Major topics in bold
Adenosine TriphosphateAnimals
Calcium
Cardiac Output, Low
Cardiotonic Agents
Creatine Kinase
Dinitrophenols
Female
Ion Channel Gating
Isoproterenol
Male
Mice
Mitochondria
Myocardium
Myocytes, Cardiac
Patch-Clamp Techniques
Potassium Channels
Transforming Growth Factor alpha
Transgenes
Uncoupling Agents
Ventricular Remodeling
