Platelet GARP-dependent activation of TGF-β1 limits inflammation and promotes cardiac repair after myocardial infarction

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Abstract Platelets are increasingly recognized as active regulators of inflammation beyond their canonical hemostatic functions. Although platelets rapidly accumulate in the injured myocardium after myocardial infarction (MI), the mechanisms by which they coordinate the inflammatory response remain poorly understood. Glycoprotein A repetitions predominant (GARP) is a membrane receptor that presents latent transforming growth factor-β1 (TGF-β1) on activated platelets and supports its activation. Given the central role of TGF-β1 in inflammation and tissue repair, we hypothesized that platelet GARP-dependent activation of TGF-β1 regulates inflammatory resolution and repair after MI. Using mice with megakaryocyte-and platelet-specific Garp deletion, we demonstrate that loss of platelet GARP selectively impaired generation of bioactive TGF-β1 without altering platelet reactivity. Following permanent coronary artery ligation, platelet-specific Garp deficiency markedly increased mortality from ventricular rupture and exacerbated adverse left ventricular remodeling, independent of initial infarct size. Transcriptomic and histological analyses revealed heightened endothelial cell activation, increased leukocyte recruitment, delayed inflammatory resolution, and defective extracellular matrix deposition in the absence of platelet GARP. Mechanistically, platelet GARP-dependent TGF-β1 signaling restrained endothelial activation after MI. Together, these findings identify platelet GARP-mediated activation of TGF-β1 as a critical platelet-intrinsic counter-regulatory checkpoint that limits endothelial-driven inflammation and promotes infarct stabilization. Our study reveals an unexpected protective immunoregulatory function of platelets in cardiac repair after ischemic injury.

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