Frontiers in Cell and Developmental Biology (Oct 2020)
RAD-Deficient Human Cardiomyocytes Develop Hypertrophic Cardiomyopathy Phenotypes Due to Calcium Dysregulation
- Ya’nan Li,
- Ya’nan Li,
- Yun Chang,
- Yun Chang,
- Xiaolei Li,
- Xiaowei Li,
- Xiaowei Li,
- Jian Gao,
- Yafei Zhou,
- Fujian Wu,
- Fujian Wu,
- Rui Bai,
- Rui Bai,
- Tao Dong,
- Tao Dong,
- Shuhong Ma,
- Shuhong Ma,
- Siyao Zhang,
- Siyao Zhang,
- Wen-Jing Lu,
- Wen-Jing Lu,
- Xiaoqiu Tan,
- Yongming Wang,
- Feng Lan,
- Feng Lan,
- Feng Lan
Affiliations
- Ya’nan Li
- Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling-Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Anzhen Hospital, Capital Medical University, Beijing, China
- Ya’nan Li
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
- Yun Chang
- Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling-Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Anzhen Hospital, Capital Medical University, Beijing, China
- Yun Chang
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
- Xiaolei Li
- Department of Cardiology, Heart Center, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Xiaowei Li
- Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling-Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Anzhen Hospital, Capital Medical University, Beijing, China
- Xiaowei Li
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
- Jian Gao
- Experimental Medicine, Faculty of Medicine, Vancouver, BC, Canada
- Yafei Zhou
- Key Laboratory of Medical Electrophysiology of the Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- Fujian Wu
- Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling-Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Anzhen Hospital, Capital Medical University, Beijing, China
- Fujian Wu
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
- Rui Bai
- Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling-Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Anzhen Hospital, Capital Medical University, Beijing, China
- Rui Bai
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
- Tao Dong
- Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling-Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Anzhen Hospital, Capital Medical University, Beijing, China
- Tao Dong
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
- Shuhong Ma
- Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling-Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Anzhen Hospital, Capital Medical University, Beijing, China
- Shuhong Ma
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
- Siyao Zhang
- Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling-Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Anzhen Hospital, Capital Medical University, Beijing, China
- Siyao Zhang
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
- Wen-Jing Lu
- Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling-Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Anzhen Hospital, Capital Medical University, Beijing, China
- Wen-Jing Lu
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
- Xiaoqiu Tan
- Key Laboratory of Medical Electrophysiology of the Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
- Yongming Wang
- The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Feng Lan
- Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling-Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Anzhen Hospital, Capital Medical University, Beijing, China
- Feng Lan
- Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing, China
- Feng Lan
- State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- DOI
- https://doi.org/10.3389/fcell.2020.585879
- Journal volume & issue
-
Vol. 8
Abstract
Ras associated with diabetes (RAD) is a membrane protein that acts as a calcium channel regulator by interacting with cardiac L-type Ca2 + channels (LTCC). RAD defects can disrupt intracellular calcium dynamics and lead to cardiac hypertrophy. However, due to the lack of reliable human disease models, the pathological mechanism of RAD deficiency leading to cardiac hypertrophy is not well understood. In this study, we created a RRAD–/– H9 cell line using CRISPR/Cas9 technology. RAD disruption did not affect the ability and efficiency of cardiomyocytes differentiation. However, RAD deficient hESC-CMs recapitulate hypertrophic phenotype in vitro. Further studies have shown that elevated intracellular calcium level and abnormal calcium regulation are the core mechanisms by which RAD deficiency leads to cardiac hypertrophy. More importantly, management of calcium dysregulation has been found to be an effective way to prevent the development of cardiac hypertrophy in vitro.
Keywords
- RRAD knockout
- RAD deficiency
- HCM
- L-type Cacpsdummy2+ channels
- calcium handling
- calcium channel blocker
