iScience (Jul 2024)
MBNL2 promotes aging-related cardiac fibrosis via inhibited SUMOylation of Krüppel-like factor4
- Jing Lu,
- Qi Zhao,
- Lu Wang,
- Jiahao Li,
- Hongyan Wang,
- Lin Lv,
- Meng Yuan,
- Qiuyu Chen,
- Zixin Zhang,
- Dankun Luo,
- Siqi Sheng,
- Keying Yuan,
- Guannan Liu,
- Mingyu Liu,
- Yuanqi Shi,
- Yuanyuan Guo,
- Zengxiang Dong
Affiliations
- Jing Lu
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China; The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Qi Zhao
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China; The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Lu Wang
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Jiahao Li
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China; The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Hongyan Wang
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China; The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Lin Lv
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China; The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China; Experimental Animal Center, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
- Meng Yuan
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China; The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Qiuyu Chen
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Zixin Zhang
- College of Bioinformatics Science and Technology, Harbin Medical University, Health Care Road, Nangang District, Harbin 150081, China
- Dankun Luo
- Department of General Surgery, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China
- Siqi Sheng
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Keying Yuan
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China; The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Guannan Liu
- Department of Pharmacy, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China; The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Mingyu Liu
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China
- Yuanqi Shi
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China; Corresponding author
- Yuanyuan Guo
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China; Department of Cardiology, Department of Geriatrics, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China; Corresponding author
- Zengxiang Dong
- The Key Laboratory of Cardiovascular Disease Acousto-Optic Electromagnetic Diagnosis and Treatment in Heilongjiang Province, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin150001, China; NHC Key Laboratory of Cell Transplantation, The First Affiliated Hospital of Harbin Medical University, Youzheng Street, Nangang District, Harbin 150001, China; Corresponding author
- Journal volume & issue
-
Vol. 27,
no. 7
p. 110163
Abstract
Summary: Aging-related cardiac fibrosis represents the principal pathological progression in cardiovascular aging. The Muscleblind-like splicing regulator 2 (MBNL2) has been unequivocally established as being associated with cardiovascular diseases. Nevertheless, its role in aging-related cardiac fibrosis remains unexplored. This investigation revealed an elevation of MBNL2 levels in the aged heart and senescent cardiac fibroblasts. Notably, the inhibition of MBNL2 demonstrated a capacity to mitigate H2O2-induced myofibroblast transformation and aging-related cardiac fibrosis. Further mechanistic exploration unveiled that aging heightened the expression of SENP1 and impeded the SUMO1 binding with KLF4, and SUMOylation of KLF4 effectively increased by the inhibition of MBNL2. Additionally, the inhibition of TGF-β1/SMAD3 signaling attenuated the impact of over-expression of MBNL2 in inducing senescence and cardiac fibrosis. MBNL2, by orchestrating SUMOylation of KLF4, upregulating the TGF-β1/SMAD3 signaling pathway, emerges as a significant promoter of aging-related cardiac fibrosis. This discovery identifies a novel regulatory target for managing aging-related cardiac fibrosis.
