Caspase-1 regulate AngII-induced cardiomyocyte hypertrophy via upregulation of IL-1β

Abstract

Cardiac hypertrophy is a compensatory response to stress or stimuli, which results in arrhythmia and heart failure. Although multiple molecular mechanisms have been identified, cardiac hypertrophy is still difficult to treat. Pyroptosis is a caspase-1 dependent pro-inflammatory programmed cell death. Caspase-1 is involved in various types of diseases, including hepatic injury, cancers, and diabetes related complications. However, the exact role of caspase-1 in cardiac hypertrophy is yet to be discovered. The present study aimed to explore the possible role of caspase-1 in pathogenesis of cardiac hypertrophy. We established cardiac hypertrophy models both in vivo and in vitro to detect the expression of caspase-1 and IL-1β. The results showed that caspase-1 and IL-1β expression levels were significantly upregulated during cardiac hypertrophy. Subsequently, caspase-1 inhibitor was co-administered with angiotensin II (Ang II) in cardiomyocytes to observe whether it could attenuate cardiac hypertrophy. Results showed that caspase-1 attenuated the pro-hypertrophic effect of Ang II, which was related to the downregulation of caspase-1 and IL-1β. In conclusion, our results provide a novel evidence that caspase-1 mediated pyroptosis is involved in cardiac hypertrophy, and the inhibition of caspase-1 will offer a therapeutic potential against cardiac hypertrophy.

Keywords: Cardiac hypertrophy; IL-1β; caspase-1; pyroptosis.

Figure 1. The cleaved caspase-1 and IL-1β expression were up-regulated in myocardium from TAC mice model

(A) The histopathological changes in Sham and TAC groups. (B) The immunohistochemical staining of cleaved caspase-1 and IL-1β in Sham and TAC groups. (C,D) Caspase-1 and IL-1β mRNA expression levels were up-regulated in myocardium form TAC operated mice. (E,F). Cleaved caspase-1 and IL-1β protein expression levels were up-regulated in myocardium form TAC operated mice. GAPDH served as the internal control. *P<0.05 compared with Sham, ***P<0.001 compared with Sham; n=5.

Figure 2. Ang II up-regulates cleaved caspase-1 and IL-1β expression in cardiomyocytes

(A,B) Caspase-1 and IL-1β mRNA expression levels were up-regulated in cardiomyocytes treated with Ang II. (C,D) Cleaved caspase-1 and IL-β protein expression levels were up-regulated in cardiomyocytes treated with Ang II. GAPDH served as the internal control. *P<0.05 compared with Control, **P<0.01 compared with Control; n=3.

Figure 3. Caspase-1 inhibitor down-regulates cleaved caspase-1 and IL-1β expression in Ang II treated cardiomyocytes

(A,B) Caspase-1 inhibitor down-regulates caspase-1 and IL-1β mRNA expression levels in Ang II-treated cardiomyocytes. (C,D) Caspase-1 inhibitor down-regulates caspase-1 and IL-1β protein expression levels in Ang II-treated cardiomyocytes. GAPDH served as the internal control. **P<0.01 compared with Control, ***P<0.001 compared with Control, ^#P<0.05 compared with Ang II, ^##P<0.01 compared with Ang II,^###P<0.001 compared with Ang II; n=3.

Figure 4. Caspase-1 inhibitor attenuates Ang II-induced hypertrophy in cardiomyocytes

(A) Representative images of α-actinin and Hoechst staining in cardiomyocytes. (B) The statistical results of cardiomyocytes surface area in each group. (C) ANP mRNA expression in cardiomyocytes. (D) BNP mRNA expression in cardiomyocytes. (E) β-MHC mRNA expression in cardiomyocytes. GAPDH served as the internal control. **P<0.01 compared with Control, ***P<0.001 compared with Control, ^#P<0.05 compared with Ang II, ^##P<0.01 compared with Ang II, ^###P<0.001 compared with Ang II; for (B), n=100 from nine separated fields; for (C–E), n=3.