Low-dose Aspirin prevents hypertension and cardiac fibrosis when thromboxane A2 is unrestrained.
Pharmacol Res
; 170: 105744, 2021 08.
Article
em En
| MEDLINE
| ID: mdl-34182131
ABSTRACT
Enhanced platelet activation has been reported in patients with essential hypertension and heart failure. The possible contribution of platelet-derived thromboxane (TX)A2 in their pathophysiology remains unclear. We investigated the systemic TXA2 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 TXA2 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 TXA2 generation. In essential hypertensive patients, systemic biosynthesis of TXA2 [assessed by measuring its urinary metabolites (TXM) reflecting predominant platelet source] was enhanced together with higher gene expression of circulating leukocyte TP and TGF-ß, vs. normotensive controls. Similarly, in hypertensive mice with prostacyclin (PGI2) 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-ß) was found. Low-dose Aspirin administration caused a selective inhibition of platelet TXA2 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 TXA2 induced profibrotic gene expression, including TGF-ß1. In conclusion, our results support tailoring low-dose Aspirin treatment in hypertensive patients with unconstrained TXA2/TP pathway to reduce blood pressure and prevent early cardiac fibrosis.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tromboxano A2
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Plaquetas
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Pressão Sanguínea
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Inibidores da Agregação Plaquetária
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Aspirina
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Miócitos Cardíacos
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Hipertensão Essencial
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Antifibróticos
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Cardiomiopatias
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Anti-Hipertensivos
Tipo de estudo:
Etiology_studies
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Observational_studies
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Risk_factors_studies
Limite:
Adult
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Pharmacol Res
Ano de publicação:
2021
Tipo de documento:
Article