Platelets Promote Ang II (Angiotensin II)-Induced Atrial Fibrillation by Releasing TGF-β1 (Transforming Growth Factor-β1) and Interacting With Fibroblasts

Abstract

Hypertension is a risk factor of atrial fibrillation (AF), and a certain number of patients with hypertension were found with an enlarged left atrium. Platelet activation is found in patients with hypertension or pressure overload/Ang II (angiotensin II)-induced hypertensive animal models and contribute to ventricular fibrosis. Whether hypertension-induced atrial fibrosis is mediated by platelets remains unknown. Our previous experimental data showed that platelet-derived TGF-β1 (transforming growth factor-β1) was reduced in patients with hypertensive AF. The present study is to investigate whether platelet-derived TGF-β1 promotes Ang II-induced atrial fibrosis and AF. Platelet activation and atrial platelet accumulation were measured in sinus rhythm controls, normotensive AF, and patients with hypertensive AF. Ang II (1500 ng/kg per minute, 3 weeks) infused mice with pharmacological (clopidogrel) and genetic platelet inhibition (TGF-β1 deletion in platelets) were used. Platelet activation, atrial structural remodeling, atrial electrical transmission, AF inducibility, inflammation, and fibrosis were measured in mice. We found that circulating platelets were activated in patients with hypertensive AF. A large amount of platelet was accumulated in the atriums of patients with hypertensive AF. Both clopidogrel treatment and platelet-specific deletion of TGF-β1 attenuated Ang II-induced structural remodeling, atrial electrical transmission, AF inducibility, as well as atrial inflammation and fibrosis than mice without interventions. Furthermore, clopidogrel blocked atrial platelet accumulation and platelet-fibroblast conjugation. Platelets promoted atrial fibroblast differentiation in cell culture. Profibrotic actions of platelets are largely via activation of atrial fibroblasts by releasing TGF-β1 and inducing platelet-fibroblast conjugation, and platelet inhibition is sufficient to inhibit atrial fibrosis and AF inducibility.

PU.1 inhibition attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin‐II by reducing TGF‐β1/Smads pathway activation

“… 48 Thus, Ang‐II and TGF‐β1 activation are deemed to play an important role in both atrial fibrosis and electric remodelling. 7 , 49 Additionally, Ang‐II exerts its effects by increasing TGF‐β1 expression, as Ang‐II is unable to induce cardiac fibrosis in the absence of TGF‐β1. 1 Therefore, reducing activation of the TGF‐β1/Smads pathway is expected to abrogate the atrial fibrosis induced by Ang‐II.…”

“… 1 , 6 There is substantial evidence that angiotensin‐II (Ang‐II) can up‐regulate TGF‐β1 and collagen expression in vitro and in vivo, and Ang‐II plays an important role in atrial fibrosis and AF through its regulation of TGF‐β1. 7 , 8 , 9 , 10 , 11 Therefore, inactivation of the TGF‐β1/Smads pathway attenuates the atrial fibrosis induced by Ang‐II.…”

Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models

“…Dosing Ang II via infusion has also been reported to induce cardiac structural remodeling with increased AF vulnerability [7-10, 28, 29]. Three weeks of Ang II infusion increased heart size in C57BL/6 mice (Fig.…”

The Systemic-Immune-Inflammation Index Predicts the Recurrence of Atrial Fibrillation After Cryomaze Concomitant With Mitral Valve Surgery

“…Recently, platelets was reported the pro brotic actions through Transforming Growth Factor-β1 dependent manners. [29] SII not only contained the ratio of neutrophil and lymphocyte ratio, but contained the levels of platelets, which may re ect atrial brosis to some extent. Therefore, SII is superior to other systemic in ammation index in prognostic assessment of AF ablation in our cohort.…”