Low-dose Aspirin prevents hypertension and cardiac fibrosis when thromboxane A 2 is unrestrained.

Enhanced platelet activation has been reported in patients with essential hypertension and heart failure. The possible contribution of platelet-derived thromboxane (TX)A ₂ in their pathophysiology remains unclear. We investigated the systemic TXA ₂ biosynthesis in vivo and gene expression of its receptor TP in 22 essential hypertension patients and a mouse model of salt-sensitive hypertension. The contribution of platelet TXA ₂ biosynthesis on enhanced blood pressure (BP) and overload-induced cardiac fibrosis was explored in mice by treating with low-dose Aspirin, resulting in selective inhibition of platelet cyclooxygenase (COX)-1-dependent TXA ₂ generation. In essential hypertensive patients, systemic biosynthesis of TXA ₂ [assessed by measuring its urinary metabolites (TXM) reflecting predominant platelet source] was enhanced together with higher gene expression of circulating leukocyte TP and TGF-β, vs. normotensive controls. Similarly, in hypertensive mice with prostacyclin (PGI ₂ ) receptor (IP) deletion (IPKO) fed with a high-salt diet, enhanced urinary TXM, and left ventricular TP overexpression were detected vs. normotensive wildtype (WT) mice. Increased cardiac collagen deposition and profibrotic gene expression (including TGF-β) was found. Low-dose Aspirin administration caused a selective inhibition of platelet TXA ₂ biosynthesis and mitigated enhanced blood pressure, cardiac fibrosis, and left ventricular profibrotic gene expression in IPKO but not WT mice. Moreover, the number of myofibroblasts and extravasated platelets in the heart was reduced. In cocultures of human platelets and myofibroblasts, platelet TXA ₂ induced profibrotic gene expression, including TGF-β1. In conclusion, our results support tailoring low-dose Aspirin treatment in hypertensive patients with unconstrained TXA ₂ /TP pathway to reduce blood pressure and prevent early cardiac fibrosis.
(Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)