Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Key Laboratory of Modern Acoustics, Department of Physics, Collaborative Innovation Center of Advanced Microstructure, Nanjing University, Nanjing 210093, China.
J Zhejiang Univ Sci B. 2021 Oct 15;22(10):818-838. doi: 10.1631/jzus.B2100130.
Cardiac hypertrophy and fibrosis are major pathological manifestations observed in left ventricular remodeling induced by angiotensin II (AngII). Low-intensity pulsed ultrasound (LIPUS) has been reported to ameliorate cardiac dysfunction and myocardial fibrosis in myocardial infarction (MI) through mechano-transduction and its downstream pathways. In this study, we aimed to investigate whether LIPUS could exert a protective effect by ameliorating AngII-induced cardiac hypertrophy and fibrosis and if so, to further elucidate the underlying molecular mechanisms.
We used AngII to mimic animal and cell culture models of cardiac hypertrophy and fibrosis. LIPUS irradiation was applied in vivo for 20 min every 2 d from one week before mini-pump implantation to four weeks after mini-pump implantation, and in vitro for 20 min on each of two occasions 6 h apart. Cardiac hypertrophy and fibrosis levels were then evaluated by echocardiographic, histopathological, and molecular biological methods.
Our results showed that LIPUS could ameliorate left ventricular remodeling in vivo and cardiac fibrosis in vitro by reducing AngII-induced release of inflammatory cytokines, but the protective effects on cardiac hypertrophy were limited in vitro. Given that LIPUS increased the expression of caveolin-1 in response to mechanical stimulation, we inhibited caveolin-1 activity with pyrazolopyrimidine 2 (pp2) in vivo and in vitro. LIPUS-induced downregulation of inflammation was reversed and the anti-fibrotic effects of LIPUS were absent.
These results indicated that LIPUS could ameliorate AngII-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway, providing new insights for the development of novel therapeutic apparatus in clinical practice.
血管紧张素 II（AngII）诱导的左心室重构主要表现为心肌肥厚和纤维化。已有研究报道，低强度脉冲超声（LIPUS）通过机械转导及其下游途径改善心肌梗死后的心脏功能障碍和心肌纤维化。本研究旨在探讨 LIPUS 是否能通过改善 AngII 诱导的心肌肥厚和纤维化发挥保护作用，如果可以，进一步阐明其潜在的分子机制。
我们使用 AngII 模拟心肌肥厚和纤维化的动物和细胞培养模型。LIPUS 照射在体内从迷你泵植入前一周开始，每两天进行一次，每次 20 分钟，共持续四周；在体外，每隔 6 小时进行一次，每次 20 分钟，共两次。然后通过超声心动图、组织病理学和分子生物学方法评估心肌肥厚和纤维化程度。
我们的结果表明，LIPUS 可通过减少 AngII 诱导的炎症细胞因子释放来改善体内左心室重构和体外心肌纤维化，但对心肌肥厚的保护作用有限。鉴于 LIPUS 可响应机械刺激增加 caveolin-1 的表达，我们在体内和体外使用 pyrazolopyrimidine 2（pp2）抑制 caveolin-1 活性。LIPUS 诱导的炎症下调被逆转，LIPUS 的抗纤维化作用消失。
这些结果表明，LIPUS 通过 caveolin-1 依赖性途径减轻炎症来改善 AngII 诱导的心肌纤维化，为临床实践中新的治疗仪器的开发提供了新的思路。
