Pirfenidone attenuates cardiac hypertrophy against isoproterenol by inhibiting activation of the janus tyrosine kinase-2/signal transducer and activator of transcription 3 (JAK-2/STAT3) signaling pathway

Abstract

Cardiovascular risk factors have attracted increasing attention in recent years with the acceleration of population aging, amongst which cardiac hypertrophy is the initiating link to heart failure. Pirfenidone is a promising agent for the treatment of idiopathic pulmonary fibrosis and has recently proven to exert inhibitory effects on the inflammatory response. This study proposes to explore the potential pharmacological action of pirfenidone in treating cardiac hypertrophy in a rodent model. Four groups of mice were used in the present study: the control, ISO (5 mg/kg/day) for 7 days, pirfenidone (200 mg/kg/day) for 14 days, and spironolactone (SPI) (200 mg/kg/day) for 14 days groups. Increased heart weight index, left ventricle (LV) weight index, LV wall thickness, declined LV volume, and elevated serum levels of CK-MB, AST, and LDH were observed in ISO-challenged mice, all of which were dramatically reversed by the administration of pirfenidone or SPI. Furthermore, an elevated cross-sectional area of cardiomyocytes in the wheat germ agglutinin (WGA) staining of heart cross-sections, upregulated atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β-Myosin Heavy Chain (β-MHC), and excessively released tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) in cardiac tissues were observed in the ISO group but greatly alleviated by pirfenidone or SPI. Lastly, the promoted expression levels of p-JAK-2/JAK-2 and p-STAT3/STAT-3 in the cardiac tissues of ISO-challenged mice were significantly repressed by pirfenidone or SPI. Collectively, our data reveals a therapeutic property of pirfenidone on ISO-induced cardiac hypertrophy in mice.

TFRC in cardiomyocytes promotes macrophage infiltration and activation during the process of heart failure through regulating Ccl2 expression mediated by hypoxia inducible factor‐1α

“…Cardiac hypertrophy is an initiating link to HF which still seriously endangers human health and is lack of effective therapeutic drugs 4,5 . In this study, our group first explored the role of TFRC in pathological cardiac hypertrophy, and found that TFRC expression in the HF tissue was significantly increased and positively related to macrophage infiltration in the process of HF, indicating that TFRC plays harmful role in HF.…”

“…Cardiac hypertrophy is an initiating link to HF which still seriously endangers human health and is lack of effective therapeutic drugs. 4,5 In this study, our group first explored the role of TFRC in pathological cardiac hypertrophy, and found that TFRC expression in the HF tissue was significantly increased and positively related to macrophage infiltration in the process of HF, indicating that TFRC plays harmful role in HF. Whereas, recent study reported that TFRC was essential for heart development, and inactivation of TFRC leaded to lethal cardiomyopathy in mice with poor cardiac function, failure of mitochondrial respiration, and ineffective mitophagy, 10 suggesting that TFRC plays protective roles in lethal cardiomyopathy.…”

“…Besides, among HF patients, 51% of patients have severe HF 3 . Nowadays, several risk factors for HF have been identified, including smoking, arterial hypertension, diabetes mellitus, excess body weight, male gender, age, and cardiac hypertrophy which is considered as the initiating link to HF 4,5 . Thus, preventing pathological cardiac hypertrophy is a potential strategy for treating HF.…”

Bellidifolin ameliorates isoprenaline-induced cardiac hypertrophy by the Nox4/ROS signalling pathway through inhibiting BRD4

“…The mouse model of cardiac hypertrophy was established as previously described [ 38 ]. Briefly, ISO (5 mg/kg/day) was subcutaneously injected for seven consecutive days.…”

The protective effects of pirfenidone in preventing abdominal aortic aneurysm formation

“…In the AAA and AAA+ pirfenidone groups, AAA mice were orally dosed with normal saline and 200 mg/kg/day pirfenidone at the same volume for 28 days. [23,24]…”