Cardiac MyD88 Mediates Inflammatory Injury and Adverse Remodeling in Diabetes

Abstract Background: Hyperglycemia-associated inflammation contributes to adverse remodeling and fibrosis in diabetic heart. MyD88 is an adapter protein of many Toll-like receptors (TLRs) and is recruited to TLRs to initiate inflammatory signalling pathway in endotoxin-activated innate immunity. However, the role of MyD88 in diabetic cardiomyopathy is unknown. Methods: For genetic deficiency, cardiomyocyte-specific MyD88 knockout and littermate control mice were induced type 1 diabetes (T1D) by intraperitoneal injection of 50 mg/kg/day streptozotocin for five days consecutive and then fed for 4 moths. For pharmacological inhibition, MyD88 inhibitor LM8 were administered daily for 8 weeks by oral gavage in T1D and T2D (db/db) mice. The effect of genetic and pharmacological inhibition MyD88 to myocardial injure which were induced by 33 mM glucose in vivo.Results: In this study, we first found that MyD88 expression was increased in cardiomyocytes of diabetic mouse hearts. Cardiomyocyte-specific MyD88 knockout protected mice against hyperglycemia-induced cardiac inflammation, injury, hypertrophy, and fibrosis in T1D model. In cultured cardiomyocytes, MyD88 inhibition either by siRNA or by small-molecular inhibitor LM8 markedly blocked TLR4-MyD88 complex formation, reduced pro-inflammatory MAPKs/NF-κB cascade activation and decreased pro-inflammatory cytokine expression under high glucose condition. Moreover, pharmacologic inhibition of MyD88 by LM8 showed significantly anti-inflammatory, anti-hypertrophic and anti-fibrotic effects in the hearts of both T1D and T2D mice. These beneficial effects of MyD88 inhibition were correlated to the reduced activation of TLR4-MyD88-MAPKs/NF-κB signaling pathways in the hearts.Conclusion: Taken together, MyD88 in cardiomyocytes mediates diabetes-induced cardiac inflammatory injuries and genetic or pharmacologic inhibition of MyD88 shows significantly cardioprotective effects, indicating MyD88 as a potential therapeutic target for diabetic cardiomyopathy.