Cellular remodeling in heart failure disrupts K(ATP) channel-dependent stress tolerance.

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 A
EMBO J. 2003 22 (8): 1732-42

PMID: 12682006 · PMCID: PMC154482 · DOI:10.1093/emboj/cdg192

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.

MeSH Terms (21)

Adenosine Triphosphate Animals 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

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