MBNL2 Promotes Aging-related Cardiac Fibrosis Via Inhibited SUMOylation of Krüppel-like Factor4

Overview

Journal iScience

Publisher Cell Press

Date 2024 Jul 8

PMID 38974966

Authors

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

Soon will be listed here.

Abstract

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 HO-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.

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