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. 2022 May;13(5):12772-12782.
doi: 10.1080/21655979.2022.2073145.

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

Zhenhuan Chen  1 , Haiwen Zhou  1 , Xiantao Huang  1 , Shaoyun Wang  1 , Xiaochao Ouyang  1 , Yunxia Wang  1 , Qianqiang Cao  1 , Liu Yang  1 , Yu Tao  1 , Hengli Lai  1
Affiliations

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

Zhenhuan Chen et al. Bioengineered. 2022 May.

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.

Keywords: JAK-2/STAT-3; Pirfenidone; cardiac hypertrophy; inflammation.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Flow chart of the experimental design.
Figure 2.
Figure 2.
Pirfenidone ameliorates ISO-induced increases in heart weight. (a). Heart weight index (HWI); (b). Left ventricle weight index (LVWI) (†, p < 0.01 vs. Vehicle group; ‡, p < 0.01 vs. ISO group). n = 5 in each group.
Figure 3.
Figure 3.
Pirfenidone decreases left ventricle (LV) wall thickness and increases LV volume in mice. Left ventricle (LV)’s diastolic anterior wall thickness (LVAWd), LV systolic anterior wall thickness (LVAWs), LV diastolic posterior wall thickness (LVPWd), LV systolic posterior wall thickness (LVPWs), LV end diastolic volume (LVEDV), and LV end systolic volume (LVESV) (†, p < 0.01 vs. Vehicle group; ‡, p < 0.01 vs. ISO group). n = 5 in each group.
Figure 4.
Figure 4.
Pirfenidone modulates hemodynamic parameters in ISO-challenged mice. (a). Quantification of left ventricular pressure (Pmax) (b). Quantification of volume (Vmax); (c). Quantification of volume (Vmin); (d). Stroke work (SW) (†, p < 0.01 vs. Vehicle group; ‡, p < 0.01 vs. ISO group). n = 5 in each group.
Figure 5.
Figure 5.
Pirfenidone reduced the levels of myocardial injury markers in ISO- challenged mice. (a) Serum levels of CK-MB; (b) Serum levels of AST; (c) Serum levels of LDH (†, p < 0.01 vs. Vehicle group; ‡, p < 0.01 vs. ISO group). n = 5 in each group.
Figure 6.
Figure 6.
Pirfenidone attenuated cardiac hypertrophy in ISO-challenged mice. (a). Representative images of wheat germ agglutinin (WGA) staining of heart cross-sections and the cross-sectional area of cardiomyocytes; (b). H&E staining to investigate cardiac histopathological changes (†, p < 0.01 vs. Vehicle group; ‡, p < 0.01 vs. ISO group). n = 5 in each group.
Figure 7.
Figure 7.
Pirfenidone decreases the mRNA levels of hypertrophic markers ANP, BNP, and β-MHC in ISO-challenged mice. (a). the mRNA levels of ANP; (b). the mRNA levels of BNP; (c). the mRNA levels of β-MHC (†, p < 0.01 vs. Vehicle group; ‡, p < 0.01 vs. ISO group). n = 5 in each group.
Figure 8.
Figure 8.
Pirfenidone suppresses inflammatory response in cardiac tissues of ISO-challenged mice. (a) Cardiac TNF-α as measured by ELISA; (b) Cardiac IL-6 as measured by ELISA (†, p < 0.01 vs. Vehicle group; ‡, p < 0.01 vs. ISO group). n = 5 in each group.
Figure 9.
Figure 9.
Pirfenidone prevents the activation of the JAK-2/STAT-3 signaling pathway in cardiac tissues of ISO-challenged mice. (a). Western blot analysis of p-JAK-2, JAK-2, p-STAT-3, STAT-3, and β-actin; (b). Quantification of p-JAK-2/JAK-2 and p-STAT3/STAT-3 (†, p < 0.01 vs. Vehicle group; ‡, p < 0.01 vs. ISO group). n = 5 in each group.
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Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (82000276) , Supported by Administration of Traditional Chinese Medicine of Jiangxi Province (2020A0148), Grant for open project from State Key Laboratory of Organ Failure Research (202001).

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