Diacerein alleviates Ang II-induced cardiac inflammation and remodeling by inhibiting the MAPKs/c-Myc pathway.

Background: Heart failure is a common event in the course of hypertension. Recent studies have highlighted the key role of the non-hemodynamic activity of angiotensin II (Ang II) in hypertension-related cardiac inflammation and remodeling. A naturally occurring compound, diacerein, exhibits anti-inflammatory activities in various systems.

Hypothesis/purpose: In this study, we have examined the potential effects of diacerein on Ang II-induced heart failure.

Methods: C57BL/6 mice were administered Ang II by micro-osmotic pump infusion for 4 weeks to develop hypertensive heart failure. Mice were treated with diacerein by gavage for final 2 weeks. RNA-sequencing analysis was performed to explore the potential mechanism of diacerein.

Results: We found that diacerein could inhibit inflammation, myocardial fibrosis, and hypertrophy to prevent heart dysfunction, without the alteration of blood pressure. To explore the potential mechanism of diacerein, RNA-sequencing analysis was performed, indicating that MAPKs/c-Myc pathway is involved in that cardioprotective effects of Diacerein. We further confirmed that diacerein inhibits Ang II-activated MAPKs/c-Myc pathway to reduce inflammatory response in mouse hearts and cultured cardiomyocytes. Deficiency of MAPKs or c-Myc in cardiomyocytes abolished the anti-inflammatory effects of diacerein.

Conclusion: Our results indicate that diacerein protects hearts in Ang II-induced mice through inhibiting MAPKs/c-Myc-mediated inflammatory responses, rendering diacerein a potential therapeutic candidate agent for hypertensive heart failure.