PMID- 34101831 OWN - NLM STAT- MEDLINE DCOM- 20220112 LR - 20240226 IS - 1097-4652 (Electronic) IS - 0021-9541 (Linking) VI - 236 IP - 12 DP - 2021 Dec TI - alphaB-crystallin/HSPB2 is critical for hyperactive mTOR-induced cardiomyopathy. PG - 8110-8121 LID - 10.1002/jcp.30465 [doi] AB - Even though aberrant mechanistic target of rapamycin (mTOR) signaling is known to cause cardiomyopathy, its underlying mechanism remains poorly understood. Because augmentation of alphaB-crystallin and hspB2 was presented in the cortical tubers and lymphangioleiomyomatosis of tuberous sclerosis complex patients, we deciphered the role of alphaB-crystallin and its adjacent duplicate gene, hspB2, in hyperactive mTOR-induced cardiomyopathy. Cardiac Tsc1 deletion (T1-hKO) caused mouse mTOR activation and cardiomyopathy. Overexpression of alphaB-crystallin and hspB2 was presented in the hearts of these mice. Knockout of alphaB-crystallin/hspB2 reversed deficient Tsc1-mediated fetal gene expression, mTOR activation, mitochondrial damage, cardiomyocyte vacuolar degeneration, cardiomyocyte size, and fibrosis of T1-hKO mice. These cardiac-Tsc1; alphaB-crystallin; hspB2 triple knockout (tKO) mice had improved cardiac function, smaller heart weight to body weight ratio, and reduced lethality compared with T1-hKO mice. Even though activated mTOR suppressed autophagy in T1-hKO mice, ablation of alphaB-crystallin and hspB2 failed to restore autophagy in tKO mice. mTOR inhibitors suppressed alphaB-crystallin expression in T1-hKO mice and rat cardiomyocyte line H9C2. Starvation of H9C2 cells activated autophagy and suppressed alphaB-crystallin expression. Since inhibition of autophagy restored alphaB-crystallin expression in starved H9C2 cells, autophagy is a negative regulator of alphaB-crystallin expression. mTOR thus stimulates alphaB-crystallin expression through suppression of autophagy. In conclusion, alphaB-crystallin and hspB2 play a pivotal role in Tsc1 knockout-related cardiomyopathy and are therapeutic targets of hyperactive mTOR-associated cardiomyopathy. CI - (c) 2021 Wiley Periodicals LLC. FAU - Wang, Lianmei AU - Wang L AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. AD - Safety Research Center of Injectable Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China. FAU - Wang, Fang AU - Wang F AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. FAU - Liu, Kemei AU - Liu K AD - Department of Cardiovascular Medicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. AD - Department of Coronary Heart Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Long, Caifeng AU - Long C AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. FAU - Chen, Yi AU - Chen Y AD - Department of Coronary Heart Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. FAU - Li, Chunjia AU - Li C AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. FAU - Li, Li AU - Li L AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. FAU - Liu, Fangming AU - Liu F AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. FAU - Zhang, Xinyu AU - Zhang X AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. FAU - Jing, Yanling AU - Jing Y AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. FAU - Wang, Yanan AU - Wang Y AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. FAU - Liang, Aihua AU - Liang A AD - Safety Research Center of Injectable Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China. FAU - Yan, Hongbing AU - Yan H AD - Department of Coronary Heart Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. AD - Department of Coronary Heart Disease, Fuwai Hospital, Chinese Academy of Medical Sciences, Shenzhen, China. FAU - Zhang, Hongbing AU - Zhang H AUID- ORCID: 0000-0001-6291-1027 AD - State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210608 PL - United States TA - J Cell Physiol JT - Journal of cellular physiology JID - 0050222 RN - 0 (Crystallins) RN - 0 (HSP27 Heat-Shock Proteins) RN - 0 (Heat-Shock Proteins) RN - 0 (Hspb2 protein, mouse) RN - 0 (MTOR Inhibitors) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Animals MH - Cardiomyopathies/drug therapy/genetics/*metabolism MH - Crystallins/*metabolism MH - HSP27 Heat-Shock Proteins/drug effects/genetics/*metabolism MH - Heat-Shock Proteins/drug effects/*metabolism MH - MTOR Inhibitors/pharmacology MH - Mice, Knockout MH - Myocytes, Cardiac/drug effects/*metabolism MH - Promoter Regions, Genetic/genetics MH - TOR Serine-Threonine Kinases/drug effects/metabolism MH - Mice OTO - NOTNLM OT - TSC1 OT - cardiomyopathy OT - hspB2 OT - mTOR OT - alphaB-crystallin EDAT- 2021/06/09 06:00 MHDA- 2022/01/13 06:00 CRDT- 2021/06/08 17:36 PHST- 2021/04/24 00:00 [revised] PHST- 2021/01/16 00:00 [received] PHST- 2021/05/26 00:00 [accepted] PHST- 2021/06/09 06:00 [pubmed] PHST- 2022/01/13 06:00 [medline] PHST- 2021/06/08 17:36 [entrez] AID - 10.1002/jcp.30465 [doi] PST - ppublish SO - J Cell Physiol. 2021 Dec;236(12):8110-8121. doi: 10.1002/jcp.30465. Epub 2021 Jun 8.