Kcnj11 Ablation Is Associated With Increased Nitro-Oxidative Stress During Ischemia-Reperfusion Injury
Year: 2017
Type: article
Abstract: Background— Despite increased secondary cardiovascular events in patients with ischemic cardiomyopathy (ICM), the expression of innate cardiac protective molecules in the hearts of patients with ICM is incompletely characterized. Therefore, we used a nonbiased RNAseq approach to determine whether differences in cardiac protective molecules occur with ICM. Methods and Results— RNAseq analysis of human control and ICM left ventricular samples demonstrated a significant decrease in KCNJ11 expression with ICM. KCNJ11 encodes the Kir6.2 subunit of the cardioprotective K ATP channel. Using wild-type mice and kcnj11 -deficient ( kcnj11 -null) mice, we examined the effect of kcnj11 expression on cardiac function during ischemia-reperfusion injury. Reactive oxygen species generation increased in kcnj11 -null hearts above that found in wild-type mice hearts after ischemia-reperfusion injury. Continuous left ventricular pressure measurement during ischemia and reperfusion demonstrated a more compromised diastolic function in kcnj11 -null compared with wild-type mice during reperfusion. Analysis of key calcium-regulating proteins revealed significant differences in kcnj11 -null mice. Despite impaired relaxation, kcnj11 -null hearts increased phospholamban Ser16 phosphorylation, a modification that results in the dissociation of phospholamban from sarcoendoplasmic reticulum Ca 2+ , thereby increasing sarcoendoplasmic reticulum Ca 2+ –mediated calcium reuptake. However, kcnj11 -null mice also had increased 3-nitrotyrosine modification of the sarcoendoplasmic reticulum Ca 2+ -ATPase, a modification that irreversibly impairs sarcoendoplasmic reticulum Ca 2+ function, thereby contributing to diastolic dysfunction. Conclusions— KCNJ11 expression is decreased in human ICM. Lack of kcnj11 expression increases peroxynitrite-mediated modification of the key calcium-handling protein sarcoendoplasmic reticulum Ca 2+ -ATPase after myocardial ischemia-reperfusion injury, contributing to impaired diastolic function. These data suggest a mechanism for ischemia-induced diastolic dysfunction in patients with ICM.
Source: Circulation Heart Failure
Authors: Bo Zhang, Tatiana Novitskaya, Debra G. Wheeler, Zhaobin Xu, Elena Chepurko, Ryan Huttinger, Heng He, Saradhadevi Varadharaj, Jay L. Zweier, Yanna Song, Meng Xu, Frank E. Harrell, Yan Ru Su, Tarek Absi, Mark J. Kohr, Mark T. Ziolo, Dan M. Roden, Christian M. Shaffer, Cristi L. Galindo, Quinn S. Wells, Richard J. Gumina
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Vanderbilt University, Georgia Clinical and Translational Science Alliance, National Institutes of Health, National Heart, Lung, and Blood Institute, National Eye Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1197620297, G1344704808, G1688481553, G3865046396, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, G725763919, VANTAGE:Consolidation to create the Vanderbilt Technologies for Advanced Genomics, The anti-fibrotic effects of neuregulin in the heart, Effect of sarcolemmal KATP channels on ROS/RNS generation and calcium handling, Core Grant in Vision Research, G949362299
OpenAlex ID: W2603702129