TY - JOUR
T1 - Kcnj11 Ablation Is Associated with Increased Nitro-Oxidative Stress during Ischemia-Reperfusion Injury
T2 - Implications for Human Ischemic Cardiomyopathy
AU - Zhang, Bo
AU - Novitskaya, Tatiana
AU - Wheeler, Debra G.
AU - Xu, Zhaobin
AU - Chepurko, Elena
AU - Huttinger, Ryan
AU - He, Heng
AU - Varadharaj, Saradhadevi
AU - Zweier, Jay L.
AU - Song, Yanna
AU - Xu, Meng
AU - Harrell, Frank E.
AU - Su, Yan Ru
AU - Absi, Tarek
AU - Kohr, Mark J.
AU - Ziolo, Mark T.
AU - Roden, Dan M.
AU - Shaffer, Christian M.
AU - Galindo, Cristi L.
AU - Wells, Quinn S.
AU - Gumina, Richard J.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
KW - KATP channels
KW - calcium
KW - calcium-binding proteins
KW - reactive nitrogen species
KW - sarcoplasmic reticulum calcium-transporting ATPases
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UR - http://www.scopus.com/inward/citedby.url?scp=85013414442&partnerID=8YFLogxK
U2 - 10.1161/CIRCHEARTFAILURE.116.003523
DO - 10.1161/CIRCHEARTFAILURE.116.003523
M3 - Article
C2 - 28209764
AN - SCOPUS:85013414442
SN - 1941-3297
VL - 10
JO - Circulation: Heart Failure
JF - Circulation: Heart Failure
IS - 2
M1 - e003523
ER -