Cardamonin intervenes in myocardial hypertrophy progression by regulating Usp18

Background: Myocardial hypertrophy is a chronic cardiac condition that often occurs from long-term pressure or volumetric load on the heart. Propranolol hydrochloride has been employed in research on hypertension, pheochromocytoma, myocardial infarction, arrhythmias, angina pectoris, and hypertrophic cardiomyopathy. Current treatments for this condition have side effects, such as arrhythmias and myocardial cell death, thus necessitating safer and more effective alternatives. Recently, Natural Products have gained attention in drug development because of their low toxicity and high efficacy. Cardamonin, a compound derived from Chinese herbal Materials, has shown potential in inhibiting oxidative stress and inflammation, which is beneficial for cardiovascular health. Nevertheless, the impact on myocardial hypertrophy and cardiac remodeling is still uncertain METHODS: Approach We employed a transverse aortic constriction (TAC)model to simulate the pathological conditions of myocardial hypertrophy. Mice were administered varying doses of CAR (10 and 40 mg kg^-1/d), and cardiac function was assessed using techniques such as echocardiography, qPCR, Masson staining, DHE staining, immunofluorescence, and immunohistochemistry. Propranolol hydrochloride was the positive control for observing the anti-myocardial hypertrophic effects of CAR.

Results: Cardamonin significantly reduced TAC-induced myocardial hypertrophy, fibrosis, inflammation, and oxidative stress. High CAR concentrations showed better anti-myocardial remodeling effects. The anti-hypertrophic effect of cardamonin was similar to that of propranolol hydrochloride. Further investigating the mechanism of action revealed that ubiquitin-specific peptidase (USP)18, a deubiquitnating Enzyme that regulates various cellular signaling pathways, was a key downstream regulator affected by cardamonin. To confirm this, AAV9-cTNT-Usp18 and Usp18 myocardial-specific knockout mice were generated and treated with TAC. Usp18 downregulation was found to interfere with the protective effects of CAR against myocardial remodeling, whereas its overexpression enhanced these effects.

Conclusion: This study used propranolol as a positive control and provided the first in-depth exploration of the concentration-dependent effects of cardamonin on myocardial hypertrophy and cardiac remodeling. CAR is a new candidate drug for Cardiovascular Disease treatment. This comparative study provides evidence for assessing the clinical application potential of new drugs and delves into its mechanisms of action, particularly the interaction with Usp18. Comprehending these mechanisms is beneficial for formulating more targeted future treatment approaches.

Cardamonin; Fibrosis; Hypertrophy; Inflammation; Oxidative stress; Usp18.