Pirfenidone Attenuates Cardiac Fibrosis in a Mouse Model of TAC-Induced Left Ventricular Remodeling by Suppressing NLRP3 Inflammasome Formation

Abstract

Objectives: Left ventricular remodeling is a frequent complication of hypertension with no therapeutic treatment available for the subsequent onset of myocardial fibrosis. Pirfenidone is an antifibrotic small-molecular-size drug with anti-inflammatory properties that is used as a treatment for fibrotic diseases, but its effects on hypertension-induced myocardial fibrosis are unknown. Therefore, we tested whether pirfenidone could ameliorate hypertension-induced left ventricular remodeling and whether hypertension-induced NLRP3 (Nod-like receptor pyrin domain containing 3), a critical protein in NLRP3 inflammasome formation, is involved in the therapeutic mechanism. Methods: A TAC-induced mouse model of hypertension and left ventricular hypertrophy was treated with pirfenidone, and survival, collagen deposition by histopathologic examination, heart function by echocardiography, concentrations of fibrosis-related inflammatory cytokines TGF-β₁, IL-1β in heart homogenate and in vitro cell cultures by ELISA, levels of ROS and inflammatory cells by flow cytometry, and levels of NLRP3 by Western blotting and immunohistochemistry were measured. Results: Pirfenidone increased the survival rate and attenuated myocardial fibrosis and inflammatory mediators in the TAC-induced hypertension-complicated left ventricular remodeling mouse model. The inhibition of NLRP3 expression by pirfenidone attenuated the expression of IL-1β and IL-1β-induced inflammatory and profibrotic responses. Conclusions: Pirfenidone may be useful in the treatment of hypertension-induced myocardial fibrosis by inhibiting NLRP3-induced inflammation and fibrosis.

Pirfenidone and the Inflammasome: Getting to the Heart of Cardiac Remodeling

“…In the present study, Wang et al [1] provide important new data suggesting that pirfenidone may be an effective therapy for the treatment of pressure overload-induced myocardial fibrosis. Using a thoracic aortic constriction (TAC) mouse model, they report that pirfenidone initiated 10 days after surgery reduced left ventricular remodeling and subsequent fibrosis.…”

“…Effective treatments for fibrosis remain elusive due in part to the involvement of pleiotropic pathways that are challenging to target therapeutically, although hope remains for a ‘magic bullet' capable of attenuating fibrosis regardless of the tissue. In this issue of Cardiology , Wang et al [1] demonstrate that the anti-inflammatory small-molecule drug pirfenidone, currently used for idiopathic pulmonary fibrosis (IPF), may be efficacious for the treatment of cardiac fibrosis.…”

Getting to the Heart of the Matter

“…It is interesting to note that perfinidone, a broad anti-inflammatory effect, has an effect blocking TGF-β and Ang-II-induced fibrosis. [93][94][95] Clinical trials examining appropriate end points of cardiac fibrosis (eg, levels of serum procollagen type I carboxyterminal peptide or CCN2) are warranted; however, development of more specific agents is likely to be of benefit to minimize any potential side effects. Thus, recent work elucidating the signaling mechanisms underlying fibrotic signaling pathways is useful.…”

A primer on current progress in cardiac fibrosis

“…To this end, pirfenidone has been shown to suppress inflammasome formation in cardiac remodeling induced by pressure overload (Roche and Czubryt 2013;Wang et al 2013). Thus it is possible that pirfenidone exerts its action, not directly on the intracellular mechanism of fibrosis, but rather on inflammation that activates the fibrotic process upstream of these pathways.…”