单位：[1]Department of Cardiology, 2nd Xiangya Hospital Central South University, 139 Renmin Middle Road, Changsha, Hunan 410011, China[2]Department of Anesthesiology, Peking UnionHospital, Peking Union Medical College and Chinese Academy of Medical Science, 1 Shuaifuyuan, Wangfujin, Dongcheng District, Beijing 100730, China[3]Department of Anesthesiology,China-Japan Friendship Hospital, 2 Yinghuanyuan East Street, Chaoying District, Beijing 100029, China[4]Department of General Surgery, 2nd Xiangya Hospital, 139 Renmin Middle Road,Central South University, Changsha, Hunan 410011, China[5]Department of Anesthesiology, University of Pennsylvania Perelman School of Medicine, 3620 Hamilton Walk, Philadelphia,PA 19104, USA[6]Department of Anesthesiology, South China University School of Medicine, 69 Chuanshan Road, Shigu District, Hengyang, Hunan 421001, China[7]Department ofChemistry, University of Pennsylvania School of Arts and Sciences, 231 S. 34 Street, Philadelphia, PA 19104, USA[8]Department of Molecular and Comparative Pathobiology, JohnsHopkins University School of Medicine, 733 N. Broadway, MRB 807, Baltimore, MD 21205, USA[9]Division of Cardiology, Department of Medicine, University of California San Francisco,555 Mission Bay Blvd South, Smith Cardiovascular Research Building, 452K, San Francisco, CA 94158, USA[10]Department of Anesthesiology and Critical Care Medicine, JohnsHopkins University School of Medicine, 1800 Orleans Street, Zayed Tower 6208, Baltimore, MD 21287, USA
Aims Increased myofilament contractility is recognized as a crucial factor in the pathogenesis of hypertrophic cardiomyopathy (HCM). Direct myofilament desensitization might be beneficial in preventing HCM disease progression. Here, we tested whether the small molecule fropofol prevents HCM phenotype expression and disease progression by directly depressing myofilament force development. Methods and results Force, intracellular Ca2+, and steady-state activation were determined in isolated trabecular muscles from wild-type (WT) and transgenic HCM mice with heterozygous human alpha-myosin heavy chain R403Q mutation (alpha MHC 403/+). alpha MHC 403/+ HCM mice were treated continuously with fropofol by intraperitoneal infusion for 12weeks. Heart tissue was analysed with histology and real-time PCR of prohypertrophic and profibrotic genes. Fropofol decreased force in a concentration-dependent manner without significantly altering [Ca2+](i) in isolated muscles from both WT and alpha MHC 403/+ HCM mouse hearts. Fropofol also depressed maximal Ca2+-activated force and increased the [Ca2+](i) required for 50% activation during steady-state activation. In whole-animal studies, chronic intra-abdominal administration of fropofol prevented hypertrophy development and diastolic dysfunction. Chronic fropofol treatment also led to attenuation of prohypertrophic and profibrotic gene expression, reductions in cell size, and decreases in tissue fibrosis. Conclusions Direct inhibition of myofilament contraction by fropofol prevents HCM disease phenotypic expression and progression, suggesting that increased myofilament contractile force is the primary trigger for hypertrophy development and HCM disease progression.
基金：
Advancing ACCM Research (StAAR) Award from the Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine; AHAGIA [17GRNT33670387]; NIH-IGMS [GM055867, GM008076, INDS NS080519]
医学