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ADAM and ADAMTS proteases as integrative hubs in heart failure pathogenesis and therapy
Xinyu Wang1, Yujie He2, Yuyan Wang2
1Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou 646000, Sichuan, China.
Insights
This review explores how ADAM and ADAMTS metalloproteinases integrate inflammation and fibrosis in heart failure (HF). Targeting these proteases offers new precision medicine strategies for cardiovascular diseases (CVDs).
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- Heart failure (HF) involves complex cellular disruptions beyond traditional neurohormonal pathways.
- ADAM and ADAMTS metalloproteinases are increasingly recognized as key regulators of pathological processes in HF.
Purpose of the Study:
- To present a dual integrative framework for understanding the role of metalloproteinases in HF.
- To highlight the potential of these proteases as therapeutic targets and biomarkers in cardiovascular diseases (CVDs).
Main Methods:
- Review of current scientific literature on metalloproteinases in HF.
- Analysis of mechanistic insights into protease function across pathological axes (inflammation, fibrosis, hypertrophy, etc.).
Main Results:
- ADAM and ADAMTS proteases act as central integrators of inflammatory, fibrotic, and hypertrophic pathways in HF.
- Individual proteases, like ADAM17, can coordinate multiple pathological axes with both detrimental and protective effects.
- These proteases show potential as diagnostic and prognostic biomarkers for CVDs.
Conclusions:
- A protease-centered framework reveals opportunities for precision intervention in HF.
- Selective inhibition of specific metalloproteinases may overcome limitations of broad-spectrum MMP inhibitors.
- Further research is needed to translate these mechanistic insights into clinical applications for CVDs.
Abstract:
Heart failure (HF) arises from multifactorial disruptions in cellular signaling, inflammation, and tissue remodeling beyond classical neurohormonal regulation. Increasing evidence highlights ADAM and ADAMTS metalloproteinases as central integrators of inflammatory, fibrotic, and hypertrophic pathways. This review establishes a dual integrative framework. Horizontally, distinct protease family members converge within each pathological axis, including inflammation, fibrosis, hypertrophy and remodeling, metabolism, and angiogenesis, to drive disease progression. Vertically, individual proteases, such as ADAM17, coordinate multiple axes through various effectors that activate distinct downstream pathways, exhibiting both detrimental and protective functions. These mechanistic insights guide the development of selective inhibitors to circumvent pitfalls associated with broad-spectrum MMP targeting. Additionally, emerging ADAM and ADAMTS family members show promise as diagnostic and prognostic biomarkers in cardiovascular diseases (CVDs). By synthesizing mechanistic depth with translational relevance, this framework reveals protease-centered opportunities for precision intervention and outlines essential future research directions.
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