Key result
SerpinA3 augmentation markedly reduces cardiac dysfunction and fibrotic remodeling from pressure overload.
Why the study?
Effective antifibrotic therapies for cardiac remodeling and HF remain limited, and the functional role and mechanisms of SerpinA3 in cardiac remodeling are poorly defined.
Does SerpinA3 improve cardiac dysfunction and prevent fibrotic remodeling in a mouse model of pressure overload-induced heart failure?
Does SerpinA3 improve cardiac dysfunction and prevent fibrotic remodeling in a mouse model of pressure overload-induced heart failure?
SerpinA3 functions as an endogenous inhibitor of TGF-β signaling that restrains cardiac fibroblast activation and fibrotic remodeling, identifying it as a promising therapeutic target for heart failure.
Hypothesis-generating for SerpinA3 augmentation in fibrotic HF; requires human validation before clinical consideration.
Background : Cardiac fibrosis is a central driver of adverse remodeling and heart failure (HF), yet effective antifibrotic therapies remain limited. SerpinA3, a member of the serine protease inhibitor family, has been implicated in cardiovascular disease, but its functional role and underlying mechanisms in cardiac remodeling are poorly defined. Methods and Results : Using a transverse aortic constriction (TAC) model, we observed that SerpinA3K expression was markedly reduced in failing mouse hearts and in circulation. Pharmacological supplementation or genetic augmentation of SerpinA3 markedly attenuated cardiac dysfunction and fibrotic remodeling in response to pressure overload. Single‐cell transcriptomic analyses further demonstrated that SerpinA3 suppresses profibrotic fibroblast programs by promoting a transition from activated and extracellular matrix–producing fibroblasts toward a quiescent, pro‐angiogenesis state. Mechanistically, SerpinA3 binds to the extracellular domain of TGF‐beta receptor type‐1, and disrupts TGF‐β receptor type‐1–TGF‐β receptor type‐2 complex formation, thereby preventing downstream Smad2/3 phosphorylation in cardiac fibroblasts. Conclusions : SerpinA3 functions as an endogenous inhibitor of TGF‐β signaling that restrains cardiac fibroblast activation and fibrotic remodeling. By targeting receptor complex assembly, SerpinA3 provides a selective mechanism to modulate profibrotic signaling. These findings identify SerpinA3 as a promising therapeutic target for HF associated with pathological fibrosis.
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Wang et al. (2026) studied Cardiac fibrosis and heart failure. SerpinA3 vs. Sterile saline or empty vector was evaluated on Cardiac dysfunction and fibrotic remodeling. Pharmacological supplementation or genetic augmentation of SerpinA3 markedly attenuated cardiac dysfunction and fibrotic remodeling in response to pressure overload.
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