Ablation Is Associated With Increased Nitro-Oxidative Stress During Ischemia-Reperfusion Injury: Implications for Human Ischemic Cardiomyopathy.

Zhang B, Novitskaya T, Wheeler DG, Xu Z, Chepurko E, Huttinger R, He H, Varadharaj S, Zweier JL, Song Y, Xu M, Harrell FE, Su YR, Absi T, Kohr MJ, Ziolo MT, Roden DM, Shaffer CM, Galindo CL, Wells QS, Gumina RJ
Circ Heart Fail. 2017 10 (2)

PMID: 28209764 · PMCID: PMC5319711 · DOI:10.1161/CIRCHEARTFAILURE.116.003523

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 expression with ICM. encodes the Kir6.2 subunit of the cardioprotective K channel. Using wild-type mice and -deficient (-null) mice, we examined the effect of expression on cardiac function during ischemia-reperfusion injury. Reactive oxygen species generation increased in -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 -null compared with wild-type mice during reperfusion. Analysis of key calcium-regulating proteins revealed significant differences in -null mice. Despite impaired relaxation, -null hearts increased phospholamban Ser16 phosphorylation, a modification that results in the dissociation of phospholamban from sarcoendoplasmic reticulum Ca, thereby increasing sarcoendoplasmic reticulum Ca-mediated calcium reuptake. However, -null mice also had increased 3-nitrotyrosine modification of the sarcoendoplasmic reticulum Ca-ATPase, a modification that irreversibly impairs sarcoendoplasmic reticulum Ca function, thereby contributing to diastolic dysfunction.

CONCLUSIONS - expression is decreased in human ICM. Lack of expression increases peroxynitrite-mediated modification of the key calcium-handling protein sarcoendoplasmic reticulum Ca-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.

© 2017 American Heart Association, Inc.

MeSH Terms (28)

Adult Animals Calcium-Binding Proteins Calcium Channels, L-Type Calcium Signaling Cardiomyopathies Case-Control Studies Disease Models, Animal Female Genetic Predisposition to Disease Humans Male Mice, Inbred C57BL Mice, Knockout Middle Aged Myocardial Infarction Myocardial Reperfusion Injury Myocardium Oxidative Stress Phenotype Potassium Channels, Inwardly Rectifying Reactive Nitrogen Species Reactive Oxygen Species Sarcoplasmic Reticulum Calcium-Transporting ATPases Tyrosine Ventricular Dysfunction, Left Ventricular Function, Left Ventricular Pressure

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