Rac1-Induced Connective Tissue Growth Factor Regulates Connexin 43 and N-Cadherin Expression in Atrial Fibrillation

Abstract

The data identify CTGF as an important mediator of atrial structural remodeling during AF. Angiotensin II activates CTGF via activation of Rac1 and nicotinamide adenine dinucleotide phosphate oxidase, leading to up-regulation of Cx43, N-cadherin, and interstitial fibrosis and therefore contributing to the signal transduction of atrial structural remodeling.

Inhibition of aldosterone synthase (CYP11B2) by torasemide prevents atrial fibrosis and atrial fibrillation in mice

“…Aldosterone directly contributes to the pathogenesis of fibrosis and AF [10-15, 26, 38]. The small GTPase-Rac1, which contributes to the generation of reactive oxygen species (ROS) by coupling to NOX1 [45], the connective tissue growth factor, the lysyl oxidase and miR-21 contribute to the aldosterone-induced signal transduction during the pathogenesis of atrial remodeling [19][20][21]25] + [26]. Here, the experiments in primary cardiac fibroblasts and 37.2%, p < 0.00017) and that fewer patients receiving torsemide died (2.2% vs. 4.5%, p < 0.05) [5].…”

“…To characterize the interaction of aldosterone synthase inhibition and CTGF, LOX, Rac1, miR-21 and atrial fibrosis during AF in vivo, transgenic mice with cardiac overexpression of constitutively active (V12) Rac1 under the control of the αMHC promoter (RacET) were studied because these mice develop spontaneous AF at high age [19][20][21]25]. RacET mice were treated long-term with torasemide (10mg/kg/day) or furosemide (40mg/kg/day) for 8 months.…”

“…Our previous studies found that the fibrosis in left atria of patients with AF is characterized by increased angiotensin II tissue concentrations as well as increased expression and activity of the small Rho-GTPase Rac1, increased expression of the connective tissue growth factor (CTGF) and increased expression of lysyl oxidase (LOX), a key enzyme of collagen crosslinking [19][20][21][22][23], as well as micro RNA-21 (miR-21), a regulator of ventricular [24] and atrial fibrosis [25]. This pro-fibrotic signalling pathway can be activated by aldosterone [26].…”

The Mineralocorticoid Receptor Promotes Fibrotic Remodeling in Atrial Fibrillation

“…The Rho kinase inhibitor Y-27632 was used at a concentration of 10 M that has been shown to down-regulate the Rho-dependent protein kinase (29). The concentration of CTGF was established in previous studies to induce pro-fibrotic changes in cardiac fibroblasts (16,18).…”

Cdon deficiency causes cardiac remodeling through hyperactivation of WNT/β-catenin signaling

“…The aberrant localization and protein expression of Cx43 have been frequently associated with cardiac remodeling and fibrosis (34,35). Whereas the presence of Cx43 at the ID is required for proper cardiac conduction, the lateralization and altered levels of this protein have been linked to cardiac pathology (36).…”