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Angiotensin II (Ang II) induces cardiac inflammation and remodeling. Emerging evidence indicates that Ang II may utilize the Toll-like receptor 4 (TLR4) signaling pathway in mediating pro-inflammatory and pro-fibrotic activities. However, the precise mechanism is poorly understood. Myeloid differentiation 2 (MD2), a molecule that physically binds to TLR4, confers lipopolysaccharide responsiveness and may also be involved in mediating the actions of Ang II. We hypothesize that MD2 plays an essential role in cardiac inflammation and remodeling induced by local Ang II, and inhibition of MD2 can attenuate Ang II-induced cardiac dysfunction. Using a specific small molecule MD2 blocker L6H21 and the MD2 knockout mice, we show that MD2 deficiency significantly reduces cardiac inflammation and subsequent fibrosis, hypertrophy, and dysfunction in mice challenged with subcutaneous injection of Ang II. In rat cardiomyocyte-like H9c2 cells as well as rat primary cardiomyocytes, inhibition of MD2 by L6H21 or siRNA knockdown suppressed the Ang II-induced TLR4 signaling pathway activation including MyD88 recruitment, and reduced cardiomyocyte hypertrophy and matrix protein expression. These pro-inflammatory activities of Ang II were independent of the AT1 receptor. Finally, we demonstrated the direct interaction between Ang II and MD2 protein via hydrogen bonds on Arg-90, Glu-92, and Asp-100. Ang II produces an inflammatory response and cardiac remodeling by directly binding to MD2, activating MD2/TLR4 complex, and recruiting MyD88. MD2 may be a new therapeutic target for Ang II-mediated cardiac inflammation and remodeling.

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Inflammation and oxidative stress play a crucial role in the development of diabetic cardiomyopathy (DCM). We previously had synthesized an Aza resveratrol–chalcone derivative 6b, of which effectively suppressing lipopolysaccharide (LPS)‐induced inflammatory response in macrophages. This study aimed to investigate the potential protective effect of 6b on DCM and underlying mechanism. In H9c2 myocardial cells, 6b potently decreased high glucose (HG)‐induced cell fibrosis, hypertrophy and apoptosis, alleviating inflammatory response and oxidant stress. In STZ‐induced type 1 diabetic mice (STZ‐DM1), orally administration with 6b for 16 weeks significantly attenuated cardiac hypertrophy, apoptosis and fibrosis. The expression of inflammatory cytokines and oxidative stress biomarkers was also suppressed by 6b distinctly, without affecting blood glucose and body weight. The anti‐inflammatory and antioxidative activities of 6b were mechanistic associated with nuclear factor‐kappa B (NF‐κB) nucleus entry blockage and Nrf2 activation both in vitro and in vivo. The results indicated that 6b can be a promising cardioprotective agent in treatment of DCM via inhibiting inflammation and alleviating oxidative stress. This study also validated the important role of NF‐κB and Nrf2 taken in the pathogenesis of DCM, which could be therapeutic targets for diabetic comorbidities.