한빛사 논문
Perundurai S. Dhandapany1,2,3,*,†, Soojeong Kang4,*, Deepak K. Kashyap1,5, Raksha Rajagopal6, Nagalingam R. Sundaresan6, Rajvir Singh4, Kumarasamy Thangaraj5,7, Shilpa Jayaprakash8, Cholenahally N. Manjunath8, Jayaprakash Shenthar8 and Djamel Lebeche4,9,10,†
1Centre for Cardiovascular Biology and Disease, Institute for Stem Cell Science and Regenerative Medicine (inStem), Bangalore, India.
2The Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR 97239, USA.
3Departments of Medicine, Molecular, and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA.
4Cardiovascular Research Center, Department of Medicine, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, USA.
5CSIR–Center for Cellular and Molecular Biology, Hyderabad, India.
6Department of Microbiology and Cell Biology, Indian Institute of Science, CV Raman Avenue, Bangalore, India.
7Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India.
8Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bengaluru, India.
9Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
10Department of Medicine, Diabetes, Obesity, and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
†Corresponding author.
*These authors contributed equally to this work as co-first authors.
Abstract
Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart muscle disease characterized by hypertrophy with preserved or increased ejection fraction in the absence of secondary causes. However, recent studies have demonstrated that a substantial proportion of individuals with HCM also have comorbid diabetes mellitus (~10%). Whether genetic variants may contribute a combined phenotype of HCM and diabetes mellitus is not known. Here, using next-generation sequencing methods, we identified novel and ultrarare variants in adiponectin receptor 1 (ADIPOR1) as risk factors for HCM. Biochemical studies showed that ADIPOR1 variants dysregulate glucose and lipid metabolism and cause cardiac hypertrophy through the p38/mammalian target of rapamycin and/or extracellular signal–regulated kinase pathways. A transgenic mouse model expressing an ADIPOR1 variant displayed cardiomyopathy that recapitulated the cellular findings, and these features were rescued by rapamycin. Our results provide the first evidence that ADIPOR1 variants can cause HCM and provide new insights into ADIPOR1 regulation.
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