Inhibition of Hmbox1 Promotes Cardiomyocyte Survival and Glucose Metabolism Through Gck Activation in Ischemia/Reperfusion Injury.

Autor:	Bei Y; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China., Zhu Y; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China., Zhou J; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China., Ai S; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China., Yao J; Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, China (J.Y.)., Yin M; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China., Hu M; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China., Qi W; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China., Spanos M; Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston (M.S., G.L.)., Li L; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China., Wei M; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China., Huang Z; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China., Gao J; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China., Liu C; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China., van der Kraak PH; Department of Pathology (P.H.v.d.K.), University Medical Center Utrecht, University Utrecht, The Netherlands., Li G; Cardiovascular Division of the Massachusetts General Hospital and Harvard Medical School, Boston (M.S., G.L.)., Lei Z; Department of Cardiology, Laboratory of Experimental Cardiology (Z.L., J.P.G.S.), University Medical Center Utrecht, University Utrecht, The Netherlands.; Division Laboratory, Central Diagnosis Laboratory Research (Z.L.), University Medical Center Utrecht, University Utrecht, The Netherlands., Sluijter JPG; Department of Cardiology, Laboratory of Experimental Cardiology (Z.L., J.P.G.S.), University Medical Center Utrecht, University Utrecht, The Netherlands.; Utrecht Regenerative Medicine Center (J.P.G.S.), University Medical Center Utrecht, University Utrecht, The Netherlands., Xiao J; Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital (Sixth People's Hospital of Nantong) and School of Life Science of Shanghai University, China (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.).; Joint International Research Laboratory of Biomaterials and Biotechnology in Organ Repair (Ministry of Education) (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.; Cardiac Regeneration and Ageing Laboratory, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Medicine (Y.B., Y.Z., J.Z., S.A., M.Y., M.H., W.Q., L.L., M.W., Z.H., J.G., C.L., J.X.), Shanghai University, China.
Jazyk:	angličtina
Zdroj:	Circulation [Circulation] 2024 Sep 10; Vol. 150 (11), pp. 848-866. Date of Electronic Publication: 2024 May 06.
DOI:	10.1161/CIRCULATIONAHA.123.067592
Abstrakt:	Background: Exercise-induced physiological cardiac growth regulators may protect the heart from ischemia/reperfusion (I/R) injury. Homeobox-containing 1 (Hmbox1), a homeobox family member, has been identified as a putative transcriptional repressor and is downregulated in the exercised heart. However, its roles in exercise-induced physiological cardiac growth and its potential protective effects against cardiac I/R injury remain largely unexplored. Methods: We studied the function of Hmbox1 in exercise-induced physiological cardiac growth in mice after 4 weeks of swimming exercise. Hmbox1 expression was then evaluated in human heart samples from deceased patients with myocardial infarction and in the animal cardiac I/R injury model. Its role in cardiac I/R injury was examined in mice with adeno-associated virus 9 (AAV9) vector-mediated Hmbox1 knockdown and in those with cardiac myocyte-specific Hmbox1 ablation. We performed RNA sequencing, promoter prediction, and binding assays and identified glucokinase (Gck) as a downstream effector of Hmbox1. The effects of Hmbox1 together with Gck were examined in cardiomyocytes to evaluate their cell size, proliferation, apoptosis, mitochondrial respiration, and glycolysis. The function of upstream regulator of Hmbox1, ETS1, was investigated through ETS1 overexpression in cardiac I/R mice in vivo. Results: We demonstrated that Hmbox1 downregulation was required for exercise-induced physiological cardiac growth. Inhibition of Hmbox1 increased cardiomyocyte size in isolated neonatal rat cardiomyocytes and human embryonic stem cell-derived cardiomyocytes but did not affect cardiomyocyte proliferation. Under pathological conditions, Hmbox1 was upregulated in both human and animal postinfarct cardiac tissues. Furthermore, both cardiac myocyte-specific Hmbox1 knockout and AAV9-mediated Hmbox1 knockdown protected against cardiac I/R injury and heart failure. Therapeutic effects were observed when sh-Hmbox1 AAV9 was administered after I/R injury. Inhibition of Hmbox1 activated the Akt/mTOR/P70S6K pathway and transcriptionally upregulated Gck, leading to reduced apoptosis and improved mitochondrial respiration and glycolysis in cardiomyocytes. ETS1 functioned as an upstream negative regulator of Hmbox1 transcription, and its overexpression was protective against cardiac I/R injury. Conclusions: Our studies unravel a new role for the transcriptional repressor Hmbox1 in exercise-induced physiological cardiac growth. They also highlight the therapeutic potential of targeting Hmbox1 to improve myocardial survival and glucose metabolism after I/R injury. Competing Interests: None.
Databáze:	MEDLINE
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