Kcnj11 Ablation Is Associated with Increased Nitro-Oxidative Stress during Ischemia-Reperfusion Injury

Implications for Human Ischemic Cardiomyopathy

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 Kohr, Mark T. Ziolo, Dan M. Roden, Christian M. Shaffer, Cristi L. Galindo, Quinn S. Wells & 1 others Richard J. Gumina

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere003523
JournalCirculation: Heart Failure
Volume10
Issue number2
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

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Reperfusion Injury
Cardiomyopathies
Reticulum
Oxidative Stress
Calcium-Transporting ATPases
Calcium
Reperfusion
Ischemia
Myocardial Reperfusion Injury
KATP Channels
Peroxynitrous Acid
Ventricular Pressure
Myocardial Ischemia
Reactive Oxygen Species
Proteins
Phosphorylation

Keywords

  • calcium
  • calcium-binding proteins
  • KATP channels
  • reactive nitrogen species
  • sarcoplasmic reticulum calcium-transporting ATPases

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Kcnj11 Ablation Is Associated with Increased Nitro-Oxidative Stress during Ischemia-Reperfusion Injury : Implications for Human Ischemic Cardiomyopathy. / Zhang, Bo; Novitskaya, Tatiana; Wheeler, Debra G.; Xu, Zhaobin; Chepurko, Elena; Huttinger, Ryan; He, Heng; Varadharaj, Saradhadevi; Zweier, Jay L.; Song, Yanna; Xu, Meng; Harrell, Frank E.; Su, Yan Ru; Absi, Tarek; Kohr, Mark; Ziolo, Mark T.; Roden, Dan M.; Shaffer, Christian M.; Galindo, Cristi L.; Wells, Quinn S.; Gumina, Richard J.

In: Circulation: Heart Failure, Vol. 10, No. 2, e003523, 01.02.2017.

Research output: Contribution to journalArticle

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, M, Ziolo, MT, Roden, DM, Shaffer, CM, Galindo, CL, Wells, QS & Gumina, RJ 2017, 'Kcnj11 Ablation Is Associated with Increased Nitro-Oxidative Stress during Ischemia-Reperfusion Injury: Implications for Human Ischemic Cardiomyopathy', Circulation: Heart Failure, vol. 10, no. 2, e003523. https://doi.org/10.1161/CIRCHEARTFAILURE.116.003523
Zhang, Bo ; Novitskaya, Tatiana ; Wheeler, Debra G. ; Xu, Zhaobin ; Chepurko, Elena ; Huttinger, Ryan ; He, Heng ; Varadharaj, Saradhadevi ; Zweier, Jay L. ; Song, Yanna ; Xu, Meng ; Harrell, Frank E. ; Su, Yan Ru ; Absi, Tarek ; Kohr, Mark ; Ziolo, Mark T. ; Roden, Dan M. ; Shaffer, Christian M. ; Galindo, Cristi L. ; Wells, Quinn S. ; Gumina, Richard J. / Kcnj11 Ablation Is Associated with Increased Nitro-Oxidative Stress during Ischemia-Reperfusion Injury : Implications for Human Ischemic Cardiomyopathy. In: Circulation: Heart Failure. 2017 ; Vol. 10, No. 2.
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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.",
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author = "Bo Zhang and Tatiana Novitskaya and Wheeler, {Debra G.} and Zhaobin Xu and Elena Chepurko and Ryan Huttinger and Heng He and Saradhadevi Varadharaj and Zweier, {Jay L.} and Yanna Song and Meng Xu and Harrell, {Frank E.} and Su, {Yan Ru} and Tarek Absi and Mark Kohr and Ziolo, {Mark T.} and Roden, {Dan M.} and Shaffer, {Christian M.} and Galindo, {Cristi L.} and Wells, {Quinn S.} and Gumina, {Richard J.}",
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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

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.

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KW - calcium-binding proteins

KW - KATP channels

KW - reactive nitrogen species

KW - sarcoplasmic reticulum calcium-transporting ATPases

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