Loss of Trim31 Worsens Cardiac Remodeling in a Mouse Model of Heart Failure by Enhancing the Activation of the NLRP3 Inflammasome

Abstract

Tripartite motif-containing protein 31 (Trim31) is known to be involved in various pathological conditions, including heart diseases. Nonetheless, its specific involvement in heart failure (HF) has yet to be determined. In this study, we examined the function and mechanism of Trim31 in HF by using mice with cardiac-specific knockout (cKO) of Trim31. The HF mouse model was induced via the subcutaneous injection of isoproterenol (ISO). We observed a decrease in Trim31 expression in the heart tissues of mice with HF. Compared with wild-type (WT) mice, Trim31 cKO mice presented more severe characteristics of HF, including worsened cardiac dysfunction, hypertrophy, and fibrosis. However, these symptoms in Trim31 cKO mice were significantly reversed when they received an intramyocardial injection of recombinant adeno-associated virus (AAV) expressing Trim31. Excessive activation of the NLRP3 inflammasome, manifested by increased levels of NLRP3, ASC, cleaved Caspase-1, cleaved GSDMD, IL-1β, and IL-18, was observed in Trim31 cKO mice with HF. However, Trim31 overexpression effectively reversed the NLRP3 inflammasome activation in Trim31 cKO mice with HF. Selective inhibition of the NLRP3 inflammasome with the NLRP3 inhibitor MCC950 effectively reversed the worsened cardiac dysfunction, hypertrophy, and fibrosis observed in Trim31 cKO mice with HF. Overall, the findings from this study reveal a crucial role of Trim31 in HF. Trim31 deficiency may contribute to the progression of HF by promoting cardiac hypertrophy, fibrosis, and inflammation by facilitating the activation of the NLRP3 inflammasome. Therefore, Trim31 may hold significant potential as a therapeutic target for the treatment of HF.

Full text

Vol.:(0123456789)
Inflammation
https://doi.org/10.1007/s10753-024-02217-w
RESEARCH
Loss ofTrim31 Worsens Cardiac Remodeling inaMouse Model ofHeart
Failure byEnhancing theActivation oftheNLRP3 Inflammasome
FengqiDuan1· HuangjingLi2· BoLu1· XiaoboWang1· XiaojunXu1
Received: 24 July 2024 / Revised: 4 December 2024 / Accepted: 9 December 2024
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024
Abstract
Tripartite motif-containing protein 31 (Trim31) is known to be involved in various pathological conditions, including heart
diseases. Nonetheless, its specific involvement in heart failure (HF) has yet to be determined. In this study, we examined the
function and mechanism of Trim31 in HF by using mice with cardiac-specific knockout (cKO) of Trim31. The HF mouse
model was induced via the subcutaneous injection of isoproterenol (ISO). We observed a decrease in Trim31 expression in
the heart tissues of mice with HF. Compared with wild-type (WT) mice, Trim31 cKO mice presented more severe character-
istics of HF, including worsened cardiac dysfunction, hypertrophy, and fibrosis. However, these symptoms in Trim31 cKO
mice were significantly reversed when they received an intramyocardial injection of recombinant adeno-associated virus
(AAV) expressing Trim31. Excessive activation of the NLRP3 inflammasome, manifested by increased levels of NLRP3,
ASC, cleaved Caspase-1, cleaved GSDMD, IL-1β, and IL-18, was observed in Trim31 cKO mice with HF. However, Trim31
overexpression effectively reversed the NLRP3 inflammasome activation in Trim31 cKO mice with HF. Selective inhibition
of the NLRP3 inflammasome with the NLRP3 inhibitor MCC950 effectively reversed the worsened cardiac dysfunction,
hypertrophy, and fibrosis observed in Trim31 cKO mice with HF. Overall, the findings from this study reveal a crucial role
of Trim31 in HF. Trim31 deficiency may contribute to the progression of HF by promoting cardiac hypertrophy, fibrosis, and
inflammation by facilitating the activation of the NLRP3 inflammasome. Therefore, Trim31 may hold significant potential
as a therapeutic target for the treatment of HF.
Keywords Cardiac remodeling· Heart failure· Trim31· NLRP3 inflammasome
Introduction
Heart failure (HF) serves as the final phase for a variety of
heart conditions and is a significant cause of morbidity and
mortality on a global scale [1]. The global prevalence of
HF exceeds 37.7 million individuals, leading to a marked
decline in their quality of life and imposing a heavy burden
on the healthcare system [2]. Unfortunately, there has been a
stable increase in the prevalence of HF in recent years, which
is attributed to the aging population as well as the increase in
risk factors such as hypertension, diabetes, and obesity [3].
Cardiac remodeling, characterized by cardiac hypertrophy
and fibrosis, serves as the basis for the initiation and pro-
gression of HF [4]. The myocardium undergoes hypertrophy
due to neurohumoral factors and other substances that pro-
mote growth during the compensatory phase [5]. The death
of cardiomyocytes caused by myocardial injury and other
pathological changes often leads to a gradual decrease in
effective contractile units. To compensate for this loss, the
remaining cardiomyocytes undergo adaptive hypertrophy,
and there is also an increase in the deposition of the extracel-
lular matrix and the development of interstitial fibrosis [6].
Therefore, reversing pathological cardiac remodeling holds
promise as a strategy for treating HF. The identification of
novel genes involved in the regulation of cardiac remodeling
could provide new targets for the development of improved
treatment modalities, ultimately benefiting patients with HF.
Tripartite motif-containing protein 31 (Trim31) belongs
to the Trim-containing protein family and is closely associ-
ated with a variety of autoimmune and autoinflammatory
* Xiaojun Xu
xuxj@mail.sysu.edu.cn
1 Department ofHematology, The Seventh Affiliated Hospital
ofSun Yat-Sen University, Sun Yat-Sen University, No. 628
Zhenyuan Road, Shenzhen518106, Guangdong, China
2 Department ofPathophysiology, School ofMedicine, Sun
Yat-Sen University, Shenzhen518106, Guangdong, China
Content courtesy of Springer Nature, terms of use apply. Rights reserved.