Abstract
Myocardial remodeling is one of the main lesions in the late stage of chronic heart failure and seriously affects the prognosis of patients. Continuous activation of the renin-angiotensin-aldosterone system (RAAS) contributes to the development of myocardial remodeling greatly, and angiotensin II (Ang II), its main constituent, can directly lead to cardiac remodeling through an inflammatory response and oxidative stress. Since Ang II-induced myocardial remodeling is closely related to inflammation, we tried to explore whether the anti-inflammatory drug oridonin (Ori) can reverse this process and its possible mechanism. Our study investigated that hypertrophy and fibrosis can be induced after being treated with Ang II in cardiomyocytes (H9c2 cells and primary rat cardiomyocytes) and C57BL/6J mice. The anti-inflammatory drug oridonin could effectively attenuate the degree of cardiac remodeling both in vivo and vitro by inhibiting GSDMD, a key protein of intracellular inflammation which can further activate kinds of inflammation factors such as IL-1β and IL-18. We illustrated that oridonin reversed cardiac remodeling by inhibiting the process of inflammatory signaling through GSDMD. After inhibiting the expression of GSDMD in cardiomyocytes by siRNA, it was found that Ang II-induced hypertrophy was attenuated. These results suggest that oridonin is proved to be a potential protective drug against GSDMD-mediated inflammation and myocardial remodeling.
Highlights
angiotensin II (Ang II), the main component of the renin-angiotensin-aldosterone system (RAAS), contributes to numerous cardiac pathophysiological processes
We found that H9c2 cells stimulated with Ang II could exacerbate cell hypertrophy, while oridonin inhibited this effect in a concentration-dependent manner (Figure 1(d))
We validated that Ang II could promote hypertrophy in cardiomyocytes, consistent with the results from previous investigations
Summary
Ang II, the main component of the RAAS, contributes to numerous cardiac pathophysiological processes. Sustained stimulation of Ang II results in excessive vasoconstriction, abnormal hypertrophy, and fibrosis in both the vasculature and cardiac tissues [1, 2, 3]. Many studies have expounded and proved that inflammation is involved and plays a vital role in Ang II-induced myocardial remodeling [4, 5, 6]. Monocytes can be activated by various harmful stimuli, resulting in the release of kinds of cytokines. Proliferation and migration of monocytes induce inflammatory reaction, leading to interstitial fibrosis, ventricular remodeling, and eventually decreased systolic function [7]. Further investigations show that Ang II-induced myofibroblast differentiation was obstructed in NLRP3 knockout cardiac fibroblasts. Ang II-induced myocardial fibrosis was alleviated in NLRP3-/-mice, with no impact on hypertension or cardiac hypertrophy [8]
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