Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarction-induced cardiac fibrosis

Abstract

Pirfenidone (PFD), an anti-fibrotic small molecule drug, is used to treat fibrotic diseases, but its effects on myocardial infarction (MI)-induced cardiac fibrosis are unknown. The aim of this study was to determine the effects of PFD on MI-induced cardiac fibrosis and the possible underlying mechanisms in rats. After establishment of the model, animals were administered PFD by gavage for 4 weeks. During the development of MI-induced cardiac fibrosis, we found activation of a positive feedback loop between the angiotensin II type 1 receptor (AT1R)/phospho-p38 mitogen-activated protein kinase (p38 MAPK) pathway and renin-angiotensin system (RAS), which was accompanied by down-regulation of liver X receptor-α (LXR-α) expression. PFD attenuated body weight, heart weight, left ventricular weight, left ventricular systolic pressure, and ±dp/dtmax changes induced by MI, which were associated with a reduction in cardiac fibrosis, infarct size, and hydroxyproline concentration. Moreover, PFD inhibited the AT1R/p38 MAPK pathway, corrected the RAS imbalance [decreased angiotensin-converting enzyme (ACE), angiotensin II, and angiotensin II type 1 receptor expression, but increased ACE2 and angiotensin (1-7) activity and Mas expression] and strongly enhanced heart LXR-α expression. These results indicate that the cardioprotective effects of PFD may be due, in large part, to controlling the feedback loop of the AT1R/p38 MAPK/RAS axis by activation of LXR-α.

Retracted: AT1R knockdown confers cardioprotection against sepsis‐induced myocardial injury by inhibiting the MAPK signaling pathway in rats

“…Furthermore, the current study reported that AT1R gene silencing inhibits the activation of the MAPK signaling pathway in sepsis. 40 Additionally, the current study also found that inhibition of the MAPK signaling pathway suppresses inflammatory response and myocardial injury in sepsis. 33 In addition, it has been reported that inhibition of the AT1R-ERK/p38 MAPK signaling pathway relieves diabetes-induced cardiac dysfunction and improves inflammatory response.…”

Antifibrotic Agent Pirfenidone Suppresses Proliferation of Human Pancreatic Cancer Cells by Inducing G0/G1 Cell Cycle Arrest

“…Specifically, PFD was shown to be effective in various in vivo models including a rat model of myocardial infarction [5,6], a mouse model of pulmonary fibrosis [7], a mouse model of nonalcoholic steatohepatitis [8], and a rats model of renal fibrosis [9]. In agreement with in vivo model data, in vitro antiproliferative effects of PFD were also confirmed with human leiomyoma cells [10], human Tenon fibroblasts [11], and rat cardiac fibroblasts [12].…”

Modulation of subsets of cardiac B lymphocytes improves cardiac function after acute injury

“…Pirfenidone has been shown to have antifibrotic, antiinflammatory, and antioxidant properties (3), and is currently FDA approved for the treatment of idiopathic pulmonary fibrosis. Pirfenidone has also been shown to be protective in the heart in a number of different experimental models of cardiac injury including transverse aortic constriction (4,5), angiotensin II-induced cardiac hypertrophy (6), DOCA salt hypertensive cardiomyopathy (7), Duchenne muscular dystrophy-associated cardiomyopathy (8), diabetes-associated cardiomyopathy (9), tachycardia-induced cardiomyopathy (10), and myocardial infarction (11,12). While the majority of the cardioprotective effects of pirfenidone have been attributed to a reduction in cardiac fibrosis, the precise cellular target and mechanism of action for the cardioprotective effects of pirfenidone in vivo remain unknown.…”