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LncRNA ZFAS1 as a SERCA2a Inhibitor to Cause Intracellular Ca2+ Overload and Contractile Dysfunction in a Mouse Model of Myocardial Infarction.
Zhang, Ying; Jiao, Lei; Sun, Lihua; Li, Yanru; Gao, Yuqiu; Xu, Chaoqian; Shao, Yingchun; Li, Mengmeng; Li, Chunyan; Lu, Yanjie; Pan, Zhenwei; Xuan, Lina; Zhang, Yiyuan; Li, Qingqi; Yang, Rui; Zhuang, Yuting; Zhang, Yong; Yang, Baofeng.
Afiliación
  • Zhang Y; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Jiao L; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Sun L; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Li Y; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Gao Y; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Xu C; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Shao Y; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Li M; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Li C; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Lu Y; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Pan Z; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Xuan L; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Zhang Y; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Li Q; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Yang R; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Zhuang Y; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Zhang Y; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
  • Yang B; From the Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Heilongjiang, China (Ying Zhang, L.J., L.S., Y. Li, Y.G., C.X., Y.S.,
Circ Res ; 122(10): 1354-1368, 2018 05 11.
Article en En | MEDLINE | ID: mdl-29475982
ABSTRACT
RATIONALE Ca2+ homeostasis-a critical determinant of cardiac contractile function-is critically regulated by SERCA2a (sarcoplasmic reticulum Ca2+-ATPase 2a). Our previous study has identified ZFAS1 as a new lncRNA biomarker of acute myocardial infarction (MI).

OBJECTIVE:

To evaluate the effects of ZFAS1 on SERCA2a and the associated Ca2+ homeostasis and cardiac contractile function in the setting of MI. METHODS AND

RESULTS:

ZFAS1 expression was robustly increased in cytoplasm and sarcoplasmic reticulum in a mouse model of MI and a cellular model of hypoxia. Knockdown of endogenous ZFAS1 by virus-mediated silencing shRNA partially abrogated the ischemia-induced contractile dysfunction. Overexpression of ZFAS1 in otherwise normal mice created similar impairment of cardiac function as that observed in MI mice. Moreover, at the cellular level, ZFAS1 overexpression weakened the contractility of cardiac muscles. At the subcellular level, ZFAS1 deleteriously altered the Ca2+ transient leading to intracellular Ca2+ overload in cardiomyocytes. At the molecular level, ZFAS1 was found to directly bind SERCA2a protein and to limit its activity, as well as to repress its expression. The effects of ZFAS1 were readily reversible on knockdown of this lncRNA. Notably, a sequence domain of ZFAS1 gene that is conserved across species mimicked the effects of the full-length ZFAS1. Mutation of this domain or application of an antisense fragment to this conserved region efficiently canceled out the deleterious actions of ZFAS1. ZFAS1 had no significant effects on other Ca2+-handling regulatory proteins.

CONCLUSIONS:

ZFAS1 is an endogenous SERCA2a inhibitor, acting by binding to SERCA2a protein to limit its intracellular level and inhibit its activity, and a contributor to the impairment of cardiac contractile function in MI. Therefore, anti-ZFAS1 might be considered as a new therapeutic strategy for preserving SERCA2a activity and cardiac function under pathological conditions of the heart.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Calcio / ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico / ARN Largo no Codificante / Infarto del Miocardio Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Circ Res Año: 2018 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Calcio / ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico / ARN Largo no Codificante / Infarto del Miocardio Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Circ Res Año: 2018 Tipo del documento: Article