ABSTRACT
Obesity rates have rapidly increased worldwide and obesity-related diseases such as hypertension and cardiovascular diseases have become leading factors for global morbidity and mortality. Currently, there are no effective treatments that can prevent or reverse obesity long-term, and hence the prevention of obesity-related adverse effects such as hypertension is critical. Qingda granule (QDG) is a condensed Traditional Chinese Medicine (TCM) formula that has been used clinically for treating hypertension, however, its effectiveness in obesity-induced hypertension and cardiac dysfunction remains explored. Mouse models of obesity via long-term feeding of high-fat high-fructose diet (HFFD) were established to examine the effect and mechanism of QDG in protecting against obesity-induced hypertension and cardiac dysfunction. C57BL/6 mice were fed with either normal diet or HFFD over a period of 16 weeks and administered with either saline or QDG for assessment of obesity-induced blood pressure and cardiac function. QDG administration demonstrated robust anti-hypertensive effects and significantly attenuated HFFD-induced elevations in blood pressures. Moreover, QDG treatment also demonstrated robust cardioprotective effects during obesity-induced hypertension by markedly improving cardiac function and preventing cardiac hypertrophy. QDG protected against obesity-induced hypertension and cardiac dysfunction was due to its ability to prevent adverse chronic activation of Akt signaling pathway during long-term feeding of HFFD. Long-term usage of QDG treatments exhibited no observable side effects and also completely prevented obesity-induced organ damage, demonstrating the feasibility and safety of prolonged use. Our findings thus elucidated the role of QDG in preventing obesity-induced hypertension and cardiac hypertrophy via inhibiting adverse activation of Akt signaling activation. Therefore, our study provides the theoretical basis for the utilization of QDG as both a safe and effective drug in the therapeutic treatment of metabolic diseases such as obesity-induced hypertension.
ABSTRACT
BACKGROUND: Myocardial infarction (MI) is the most common cause of cardiac injury, resulting in widespread and irreversible damage to the heart. The incidence of MI gives rise to the excessive production of inflammatory cytokines that further promotes myocardial dysfunction. Wnt/ß-catenin signaling pathway is adversely activated during MI and plays an important role in the modulation of the inflammatory response following tissue injury. Huoxin pill (HXP) is a Traditional Chinese Medicine formulation that has been long used in the treatment of cardiovascular diseases, however its mechanisms of cardioprotection remain unclear. METHODS: We performed murine models of MI in order to model myocardial ischemic damage and examine the effect and underlying mechanism of HXP in protecting against myocardial ischemic injury. We further constructed conditional cardiomyocyte-specific ß-catenin knockout mice and induced surgical MI in order to better understand the role of Wnt/ß-catenin signaling following myocardial infarction in the adult heart. RESULTS: HXP administration strongly protected against cardiac ischemic injury, improved cardiac function, and markedly decreased the expression of pro-inflammatory cytokines following MI. Nuclear activation of ßcatenin resulted in significantly increased nuclear translocation and activation of NF-κB. In contrast, cardiomyocyte-specific deletion of ß-catenin decreased NF-κB activation and exhibited beneficial effects following ischemic injury. Hence, HXP protected against MI-induced ischemic injury and excessive inflammatory response via inhibiting Wnt/ßcatenin signaling. CONCLUSIONS: Our study elucidated the role of HXP in protecting against ischemic myocardial injury via preventing MI-induced inflammatory response, which was mediated by its ability to inhibit adverse Wnt/ßcatenin signaling activation. Thus, our study provides the basis for the implementation of HXP as an effective therapeutic strategy in protecting against myocardial ischemic diseases.