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LARP7 Protects Against Heart Failure by Enhancing Mitochondrial Biogenesis.
Yu, Huijing; Zhang, Fang; Yan, Pengyi; Zhang, Shasha; Lou, Yingmei; Geng, Zilong; Li, Zixuan; Zhang, Yan; Xu, Yuejuan; Lu, Yanan; Chen, Chen; Wang, Daowen; Zhu, Wei; Hu, Xinyang; Wang, Jian'an; Zhuang, Tao; Zhang, Yuzhen; Wu, Gengze; Liu, Junling; Zeng, Chunyu; Pu, William T; Sun, Kun; Zhang, Bing.
Affiliation
  • Yu H; Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).
  • Zhang F; Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).
  • Yan P; Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).
  • Zhang S; Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).
  • Lou Y; Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).
  • Geng Z; Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).
  • Li Z; Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).
  • Xu Y; Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).
  • Lu Y; Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Xin Hua Hospital, Shanghai Jiao Tong University, China (H.J.Y., F.Z., P.Y.Y., S.S.Z., Y.M.L., Z.L.G., Z.X.L., Y.J.X., Y.N.L., K.S., B.Z.).
  • Chen C; Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (C.C., D.W.W.).
  • Wang D; Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (C.C., D.W.W.).
  • Zhu W; Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China (W.Z., X.Y.H., J.A.W.).
  • Wang J; Department of Cardiology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China (W.Z., X.Y.H., J.A.W.).
  • Zhuang T; Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, China (T.Z., Y.Z.Z.).
  • Zhang Y; Renji-Med Clinical Stem Cell Research Center, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, China (Y.Z.).
  • Wu G; Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, China (T.Z., Y.Z.Z.).
  • Liu J; Department of Cardiology, Chongqing Institute of Cardiology, Chongqing Cardiovascular Clinical Research Center, Daping Hospital, The Third Military Medical University, China (G.Z.W., C.Y.Z.).
  • Pu WT; Department of Cardiology, Chongqing Institute of Cardiology, Chongqing Cardiovascular Clinical Research Center, Daping Hospital, The Third Military Medical University, China (G.Z.W., C.Y.Z.).
  • Sun K; Department of Cardiology, Boston Children's Hospital, MA (W.T.P).
  • Zhang B; Harvard Stem Cell Institute, Cambridge, MA (W.T.P).
Circulation ; 143(20): 2007-2022, 2021 05 18.
Article in En | MEDLINE | ID: mdl-33663221
ABSTRACT

BACKGROUND:

Heart failure (HF) is among the leading causes of morbidity and mortality, and its prevalence continues to rise. LARP7 (La ribonucleoprotein domain family member 7) is a master regulator that governs the DNA damage response and RNAPII (RNA polymerase II) pausing pathway, but its role in HF pathogenesis is incompletely understood.

METHODS:

We assessed LARP7 expression in human HF and in nonhuman primate and mouse HF models. To study the function of LARP7 in heart, we generated global and cardiac-specific LARP7 knockout mice. We acutely abolished LARP7 in mature cardiomyocytes by Cas9-mediated LARP7 somatic knockout. We overexpressed LARP7 in cardiomyocytes using adeno-associated virus serotype 9 and ATM (ataxia telangiectasia mutated protein) inhibitor. The therapeutic potential of LARP7-regulated pathways in HF was tested in a mouse myocardial infarction model.

RESULTS:

LARP7 was profoundly downregulated in failing human hearts and in nonhuman primate and murine hearts after myocardial infarction. Low LARP7 levels in failing hearts were linked to elevated reactive oxygen species, which activated the ATM-mediated DNA damage response pathway and promoted LARP7 ubiquitination and degradation. Constitutive LARP7 knockout in mouse resulted in impaired mitochondrial biogenesis, myocardial hypoplasia, and midgestational lethality. Cardiac-specific inactivation resulted in defective mitochondrial biogenesis, impaired oxidative phosphorylation, elevated oxidative stress, and HF by 4 months of age. These abnormalities were accompanied by reduced SIRT1 (silent mating type information regulation 2 homolog 1) stability and deacetylase activity that impaired SIRT1-mediated transcription of genes for oxidative phosphorylation and energy metabolism and dampened cardiac function. Restoring LARP7 expression after myocardial infarction by either adeno-associated virus-mediated LARP7 expression or small molecule ATM inhibitor substantially improved the function of injured heart.

CONCLUSIONS:

LARP7 is essential for mitochondrial biogenesis, energy production, and cardiac function by modulating SIRT1 homeostasis and activity. Reduction of LARP7 in diseased hearts owing to activation of the ATM pathway contributes to HF pathogenesis and restoring LARP7 in the injured heart confers myocardial protection. These results identify the ATM-LARP7-SIRT1 pathway as a target for therapeutic intervention in HF.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ribonucleoproteins / Heart Failure / Mitochondria Type of study: Risk_factors_studies Limits: Animals / Humans Language: En Journal: Circulation Year: 2021 Type: Article
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ribonucleoproteins / Heart Failure / Mitochondria Type of study: Risk_factors_studies Limits: Animals / Humans Language: En Journal: Circulation Year: 2021 Type: Article