Beta2-adrenergic receptor regulates cardiac fibroblast autophagy and collagen degradation

Abstract

Autophagy is a physiological degradative process key to cell survival during nutrient deprivation, cell differentiation and development. It plays a major role in the turnover of damaged macromolecules and organelles, and it has been involved in the pathogenesis of different cardiovascular diseases. Activation of the adrenergic system is commonly associated with cardiac fibrosis and remodeling, and cardiac fibroblasts are key players in these processes. Whether adrenergic stimulation modulates cardiac fibroblast autophagy remains unexplored. In the present study, we aimed at this question and evaluated the effects of b(2)-adrenergic stimulation upon autophagy. Cultured adult rat cardiac fibroblasts were treated with agonists or antagonists of beta-adrenergic receptors (b-AR), and autophagy was assessed by electron microscopy, GFP-LC3 subcellular distribution, and immunowesternblot of endogenous LC3. The predominant expression of b(2)-ARs was determined and characterized by radioligand binding assays using [(3)H]dihydroalprenolol. Both, isoproterenol and norepinephrine (non-selective b-AR agonists), as well as salbutamol (selective b(2)-AR agonist) increased autophagic flux, and these effects were blocked by propanolol (b-AR antagonist), ICI-118,551 (selective b(2)-AR antagonist), 3-methyladenine but not by atenolol (selective b(1)-AR antagonist). The increase in autophagy was correlated with an enhanced degradation of collagen, and this effect was abrogated by the inhibition of autophagic flux. Overall, our data suggest that b(2)-adrenergic stimulation triggers autophagy in cardiac fibroblasts, and that this response could contribute to reduce the deleterious effects of high adrenergic stimulation upon cardiac fibrosis.

Autophagy Promotes Intracellular Degradation of Type I Collagen Induced by Transforming Growth Factor (TGF)-β1

“…Our data provide the first evidence that TGF-␤1 promotes the intracellular degradation of Col-I via autophagic process to regulate the levels of Col-I. Others had previously reported that autophagy induced by the activation of ␤ 2 -adrenergic receptors enhanced the degradation of collagen in cardiac fibroblasts (10). Rapamycin, which induces autophagy by inhibiting mTOR, enhanced elimination of aggregated procollagen (9).…”

“…In heat shock protein 47 (Hsp47)-null cells, the deletion of collagen-specific molecular chaperone Hsp47 results in misfolded type I procollagens that are subjected to intracellular degradation via autophagy (9). Furthermore, enhanced degradation of Col-I correlated with increase in autophagy when the ␤ 2 -adrenergic receptor is activated in cardiac fibroblasts (10). These data strongly suggest that autophagy plays a role in the turnover of ECM through intracellular degradation of Col-I.…”

“…Proteolysis of ECM by MMPs is a major mechanism by which tissues eliminate excess ECM protein accumulation and prevent tissue fibrosis. Recent evidence suggests an additional mechanism by which Col-I, one of the major ECM components, can undergo intracellular degradation via induction of autophagy (9,10). Autophagy represents a fundamental cellular homeostatic process to degrade and recycle cellular proteins and damaged organelles.…”

Deletion of ATG5 Shows a Role of Autophagy in Salivary Homeostatic Control

“…Carbachol was utilized to stimulate saliva production in this study, since Ipr has been shown to regulate autophagy in certain tissues (Aránguiz-Urroz et al, 2011). The results of accumulated MUC5B in SLGs (Fig.…”

Autophagy: A new therapeutic target for liver fibrosis

“…Autophagy attenuates endoplasmic reticulum stress by eliminating misfolded procollagen [24] . Furthermore, Beta (2)-adrenergic stimulation triggers autophagy in cardiac fibroblasts and promotes intracellular collagen degradation and inhibits cardiac fibrosis [25] . However, this effect has been demonstrated in other organs, and whether it exhibits the same effect in liver remains unclear.…”