The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy in mice

Abstract

Pirfenidone (5-methyl-1-phenyl-2-[ 1 H]-pyridone) is an effective drug for idiopathic interstitial pneumonia that can prevent and reverse tissue fibrosis in several organs. Therefore, we investigated whether pirfenidone has a potential role in preventing angiotensin II (Ang II)-induced cardiac hypertrophy. A cardiac hypertrophic mouse model was created using an Ang II infusion (200 ng kg À1 min À1 ) in wild-type mice for 2 weeks. Mice were divided into the following three groups: a saline-infused (control) group, an Ang II infusion (vehicle) group and an Ang II infusion+pirfenidone-treated (PFD) group, which received pirfenidone (300 mg kg À1 per day) by gastric gavage during the Ang II infusion. At 2 weeks, we assessed hemodynamics and cardiac function and investigated tissue fibrosis of the myocardium histologically and genetically. Blood pressure in the vehicle group was significantly increased compared to the control group. Although blood pressure was not different between the vehicle and PFD groups, heart weight was significantly decreased in the PFD group. Echocardiography revealed that left ventricular hypertrophy was significantly increased in the vehicle group vs. the control group. Interestingly, pirfenidone significantly inhibited this effect. Continuous infusion of Ang II increased the perivascular and interstitial tissue fibrosis, and pirfenidone inhibited these fibrotic changes. Pirfenidone also inhibited Ang II-induced hypertrophy. In the vehicle group, the mRNA expressions of atrial natriuretic peptide, brain natriuretic peptide and transforming growth factor-b1 were increased, which was significantly inhibited by pirfenidone. Furthermore, the expression of mineralocorticoid receptors was attenuated by pirfenidone. These results indicate that pirfenidone might be effective as an antifibrotic drug in the treatment of cardiac hypertrophy induced by hypertension.

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

“…This correlated with reduced protein levels of ROS, TGF-β 1 , and IL-1β in the heart. Our results confirm those of a previous study that used pirfenidone to prevent left ventricular hypertrophy and perivascular and interstitial tissue fibrosis in a mouse model of angiotensin II-induced cardiac hypertrophy [8]. In that study, the inhibition of tissue fibrosis was suggested to be due to a reduction in mRNA expression of a number of profibrotic mediators including atrial natriuretic peptide, brain natriuretic peptide, and TGF-β 1 [8].…”

“…Although this is a useful property for clinical use, it was noted that it induces the formation of aneuploidy in proliferating fibroblast cells, thus restricting its use for the clinical treatment of fibrosis disorders in humans. Previous studies in mouse models have suggested that pirfenidone might have universal therapeutic antifibrosis effects in different kinds of organ fibrotic diseases [6,7,8] and, therefore, pirfenidone remains one of the best choices for the development of antifibrotic drugs with which to treat cardiac fibrosis. The aim of this study was to determine whether treatment with pirfenidone, a small-molecular drug with antifibrotic properties, could ameliorate fibrosis in a mouse model of TAC-induced left ventricular hypertrophy and myocardial remodeling.…”

“…It can attenuate the proliferation and activation of fibroblasts and the expression of profibrotic factors, such as transforming growth factor-β 1 (TGF-β 1 ) [5]. Recently, studies have focused on the beneficial effects of pirfenidone treatment for various forms of fibrotic disorders, such as hepatic, renal, cystic, and myocardial fibrosis [6,7,8]. These studies have suggested that pirfenidone might have universal therapeutic effects in different models of organ fibrosis.…”

Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice

“…To induce cardiac hypertrophy, AT-II (1000 ng kg À1 min À1 ) was continuously infused subcutaneously for 14 days via an osmotic mini-pump (ALZET, Cupertino, CA, USA) 19,20 . The control group received a saline infusion.…”

Tolvaptan Attenuates Left Ventricular Fibrosis After Acute Myocardial Infarction in Rats

“…The area of interstitial fibrosis in the marginal area of the infarct was measured as described previously (14,17). Briefly, 4-mm-thick sections were cut and stained with Sirius red stain for the measurement of the area of interstitial fibrosis.…”