Angiotensin II Induces Cardiac Edema and Hypertrophic Remodeling through Lymphatic-Dependent Mechanisms.

Jie Bai,Qiu-Yue Lin,Liangqingqing Yin,Wei-Jia Yu,Yun-Long Zhang,Hui-Hua Li,Matthew Brody

doi:10.1155/2022/5044046

Abstract

Cardiac lymphatic vessel growth (lymphangiogenesis) and integrity play an essential role in maintaining tissue fluid balance. Inhibition of lymphatic lymphangiogenesis is involved in cardiac edema and cardiac remodeling after ischemic injury or pressure overload. However, whether lymphatic vessel integrity is disrupted during angiotensin II- (Ang II-) induced cardiac remodeling remains to be investigated. In this study, cardiac remodeling models were established by Ang II (1000 ng/kg/min) in VEGFR-3 knockdown (Lyve-1Cre VEGFR-3f/−) and wild-type (VEGFR-3f/f) littermates. Our results indicated that Ang II infusion not only induced cardiac lymphangiogenesis and upregulation of VEGF-C and VEGFR-3 expression in the time-dependent manner but also enhanced proteasome activity, MKP5 and VE-cadherin degradation, p38 MAPK activation, and lymphatic vessel hyperpermeability. Moreover, VEGFR-3 knockdown significantly inhibited cardiac lymphangiogenesis in mice, resulting in exacerbation of tissue edema, hypertrophy, fibrosis superoxide production, inflammation, and heart failure (HF). Conversely, administration of epoxomicin (a selective proteasome inhibitor) markedly mitigated Ang II-induced cardiac edema, remodeling, and dysfunction; upregulated MKP5 and VE-cadherin expression; inactivated p38 MAPK; and reduced lymphatic vessel hyperpermeability in WT mice, indicating that inhibition of proteasome activity is required to maintain lymphatic endothelial cell (LEC) integrity. Our results show that both cardiac lymphangiogenesis and lymphatic barrier hyperpermeability are implicated in Ang II-induced adaptive hypertrophic remodeling and dysfunction. Proteasome-mediated hyperpermeability of LEC junctions plays a predominant role in the development of cardiac remodeling. Selective stimulation of lymphangiogenesis or inhibition of proteasome activity may be a potential therapeutic option for treating hypertension-induced cardiac remodeling.

Highlights

Cardiac remodeling is generally accepted as a determinant of heart failure (HF), a major contributor to morbidity and mortality worldwide
By stimulating VEGFR-3 knockdown (Lyve-1Cre VEGFR-3f/−) and wild-type (WT) mice and mouse lymphatic endothelial cell (LEC) stimulated with a selective proteasome inhibitor, we found that angiotensin II (Ang II) caused cardiac edema and hypertrophic remodeling accompanied by increased lymphangiogenesis and hyperpermeability in a time-dependent manner
We provide novel evidence that both lymphangiogenesis and lymphatic vessel hyperpermeability are involved in angiotensin II- (Ang II-)induced cardiac edema and hypertrophic remodeling

Summary

Introduction

Cardiac remodeling is generally accepted as a determinant of heart failure (HF), a major contributor to morbidity and mortality worldwide. This dynamic process includes many functional and structural alterations, such as cardiac contractile dysfunction, hypertrophy, interstitial fibrosis, and myocyte apoptosis [1]. Increasing evidence demonstrates that multiple factors modulate the pathogenesis of cardiac remodeling, including angiotensin II (Ang II), high salt intake, inflammation, and oxidative stress, which activate multiple molecular pathways, including the AKT/mTOR, MEK/ERK, JAK/STAT, and TGF-β/Smad pathways, thereby resulting in cardiac remodeling and dysfunction [1]. The roles of lymphatic growth (lymphangiogenesis) and function in the regulation of ischemia and pressure overload of the heart have been identified [4]. The involvement of lymphatic vessel growth and integrity in Ang II-induced cardiac remodeling is still unknown

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Conclusion