Hypertension-associated acetate deficiency enhances platelet activation and thrombosis via Olfr78
Y Chen, B Li, Y Lin, W Sha, J Li, Y Zheng, L HuAbstract
Background
Arterial thrombotic events constitute the leading cause of mortality in hypertension. Gut dysbiosis induces endothelial dysfunction and systemic inflammation, contributing to hypertension and its associated cardiovascular complications. Whether these dysbiotic microbiota metabolites in hypertension directly regulate platelet hyperactivation and thrombosis remains unclear.
Methods
Fecal microbiota transplantation, 16S rRNA sequencing and untargeted metabolomics were performed using samples from hypertensive patients. In vivo FeCl3-induced mesenteric arteriole thrombosis model, ex vivo microfluidic whole-blood perfusion assay, and in vitro platelet functional studies defined the functional effects of acetate on platelet activation. Moreover, platelet-specific olfactory receptor 78 (Olfr78)-deficient mice were employed to explore the underlying mechanisms of acetate on platelet activation.
Results
Transplantation with fecal microbiota from hypertensive patients enhanced in vivo FeCl3-injured mesenteric arteriole thrombosis and ex vivo whole blood thrombus formation compared with fecal microbiota from healthy normotensive subjects. Untargeted metabolomics revealed gut microbiota-derived acetate was decreased in patients with hypertension, and plasma acetate concentration negatively correlated with integrin αIIbβ3 activation and P-selectin exposure. Acetate demonstrated superior antiplatelet efficacy against ADP-induced aggregation, dense-granule secretion, α-granule secretion and integrin αIIbβ3 activation than collagen or thrombin-induced platelet activation. Mechanistic studies using platelet-specific Olfr78-/- mice revealed that acetate bound to and activated Olfr78, a receptor not previously reported to express in platelets, to elevate cAMP level and activate PKA, thereby increasing p-VASP and decreasing Ca2+ mobilization as well as inactivating RhoA/ROCK2/MLC signaling to inhibit platelet activation. A high-fiber diet upregulated acetate/Olfr78 signaling in platelets to suppress microvascular thrombosis and protect against myocardial injury during myocardial infarction in mice.
Conclusions
Acetate is a negative regulator of platelet hyperreactivity and thrombus formation via Olfr78 receptor, and acetate deficiency contributes to platelet hyperreactivity in hypertension. Lifestyle modifications, particularly high-fiber dietary intervention and acetate supplementation, exhibit potent antithrombotic effects in hypertension.Plasma acetate linked to thrombotic potentialStructured graphical abstract