Role of Caveolin-1 in Atrial Fibrillation as an Anti-Fibrotic Signaling Molecule in Human Atrial Fibroblasts

Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the general population; yet, the precise mechanisms resulting in AF are not fully understood. Caveolin-1 (Cav-1), the principal structural component of caveolae organelles in cardiac fibroblasts, is involved in several cardiovascular conditions; however, the study on its function in atrium, in particular, in AF, is still lacking. This report examines the hypothesis that Cav-1 confers an anti-AF effect by mediating atrial structural remodeling through its anti-fibrotic action. We evaluated the expression of Cav-1, transforming growth factor-β1 (TGF-β1), and fibrosis in atrial specimens of 13 patients with AF and 10 subjects with sinus rhythm, and found that the expression of Cav-1 was significantly downregulated, whereas TGF-β1 level, collagens I/III contents and atrial fibrosis were markedly increased, in AF. Western blot analysis demonstrated that treatment of human atrial fibroblasts (HAFs) with TGF-β1 resulted in a concentration- and time-dependent repression of Cav-1. Downregulation of Cav-1 with siRNA increased the TGF-β1-induced activation of Smad signal pathway and collagens production in HAFs. Furthermore, incubation of HAFs with the peptides derived from Cav-1 to achieve Cav-1 gain-of-function abolished the TGF-β1-induced production of collagens I/III and decreases of MMP-2/-9 expression. Therefore it was concluded that Cav-1 is an important anti-AF signaling mediator by conferring its anti-fibrotic effects in atrium.

Genetic variants associated with risk of atrial fibrillation regulate expression of PITX2, CAV1, MYOZ1, C9orf3 and FANCC

“…This association has previously been demonstrated in adipose tissue and skin in the MuTHER study [13], although not in atrial tissue. This finding, and the observation that CAV1, but not CAV2 expression levels in atria are associated with AF status in this cohort (confirming previously published studies [16]), suggests a causal role of CAV1 in AF risk. CAV1 and CAV2 are widely expressed in human tissues and encode caveolins 1 and 2, which are involved in the formation of caveolae.…”

“…Atrial fibrosis is an important component in the pathophysiology of AF [20]. Overexpression of CAV1 has been shown to reduce activity in the TGF1β signalling pathway which plays a central role in tissue fibrosis [16]. It seems possible therefore that upregulation of CAV1 activity in cardiac tissue might have a protective effect in AF.…”

Reversal of maladaptive fibrosis and compromised ventricular function in the pressure overloaded heart by a caveolin-1 surrogate peptide

“…13,25,27,29,30 Similarly, in heart fibrosis induced by cryoinjury or MI or associated with atrial fibrillation, caveolin-1 expression is low in certain cell types and is associated with ECM accumulation and impaired cardiac function. 31–33 …”

Alterations in Caveolin-1 Expression and Receptor-Operated Ca2+ Entry in the Aortas of Rats with Pulmonary Hypertension

“…Caveolae and Cav-1 are distributed ubiquitously in the vasculature, and Cav-1 is a regulatory molecule implicated in the pathogenesis of cardiovascular diseases, such as atherosclerosis [42], atrial fibrillation [43], hypertension and PH [25]. The expression and effect of Cav-1 in PH patients and animal models are a result of polymorphisms.…”