Bo Zhang1, Tatiana Novitskaya1, Debra G Wheeler1, Zhaobin Xu1, Elena Chepurko1, Ryan Huttinger1, Heng He1, Saradhadevi Varadharaj1, Jay L Zweier1, Yanna Song1, Meng Xu1, Frank E Harrell1, Yan Ru Su1, Tarek Absi1, Mark J Kohr1, Mark T Ziolo1, Dan M Roden1, Christian M Shaffer1, Cristi L Galindo1, Quinn S Wells1, Richard J Gumina2. 1. From the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute (B.Z., D.G.W., Z.X., R.H., H.H., S.V., J.L.Z.), Department of Physiology and Cell Biology (B.Z., J.L.Z., M.J.K., M.T.Z.), The Ohio State University, Columbus; Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China (B.Z.); Department of Biostatistics (Y.S., M.X., F.E.H.), Division of Clinical Pharmacology, Department of Medicine (D.M.R., C.M.S.), Division of Cardiac Surgery, Department of Surgery (T.A.), Division of Cardiovascular Medicine (T. N., E. C., Y.R.S., D.R., C.L.G., Q.S.W, R.J.G.), Department of Pharmacology and Department of Pathology, Immunology, and Microbiology (R.J.G.), Vanderbilt University Medical Center, Nashville, TN. 2. From the Division of Cardiovascular Medicine, Davis Heart and Lung Research Institute (B.Z., D.G.W., Z.X., R.H., H.H., S.V., J.L.Z.), Department of Physiology and Cell Biology (B.Z., J.L.Z., M.J.K., M.T.Z.), The Ohio State University, Columbus; Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, China (B.Z.); Department of Biostatistics (Y.S., M.X., F.E.H.), Division of Clinical Pharmacology, Department of Medicine (D.M.R., C.M.S.), Division of Cardiac Surgery, Department of Surgery (T.A.), Division of Cardiovascular Medicine (T. N., E. C., Y.R.S., D.R., C.L.G., Q.S.W, R.J.G.), Department of Pharmacology and Department of Pathology, Immunology, and Microbiology (R.J.G.), Vanderbilt University Medical Center, Nashville, TN. richard.gumina@vanderbilt.edu.
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 KATP 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 Ca2+, thereby increasing sarcoendoplasmic reticulum Ca2+-mediated calcium reuptake. However, kcnj11-null mice also had increased 3-nitrotyrosine modification of the sarcoendoplasmic reticulum Ca2+-ATPase, a modification that irreversibly impairs sarcoendoplasmic reticulum Ca2+ 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 Ca2+-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.
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 KATP 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 phospholambanSer16 phosphorylation, a modification that results in the dissociation of phospholamban from sarcoendoplasmic reticulum Ca2+, thereby increasing sarcoendoplasmic reticulum Ca2+-mediated calcium reuptake. However, kcnj11-null mice also had increased 3-nitrotyrosine modification of the sarcoendoplasmic reticulum Ca2+-ATPase, a modification that irreversibly impairs sarcoendoplasmic reticulum Ca2+ 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 Ca2+-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.
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