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Journal of Zhejiang University SCIENCE B
ISSN 1673-1581(Print), 1862-1783(Online), Monthly
2021 Vol.22 No.10 P.818-838
Low‐intensity pulsed ultrasound ameliorates angiotensin II-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway
Abstract: ObjectiveCardiac 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.
MethodsWe 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.
ResultsOur 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.
ConclusionsThese 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.
Key words: Low-intensity pulsed ultrasound (LIPUS); Caveolin-1; Cardiac fibrosis; Inflammation; Angiotensin II (AngII)
创新点：本研究首次发现LIPUS能通过机械敏感蛋白--小窝蛋白1（caveolin-1）减轻AngII引起的炎症反应，从而在体内和体外改善AngII引起的心肌纤维化。本研究为LIPUS今后在临床上用于预防和改善患者心肌纤维化损伤提供了理论依据。
方法：我们用AngII在体内和体外分别模拟心肌纤维化的动物和细胞模型。在体内，从术前1周到术后4周，每2天用LIPUS照射心前区20分钟；在体外，每隔6小时照射细胞20分钟，一共2次。然后，用超声心动图、组织病理学和分子生物学方法评价心肌肥大和纤维化水平。
结论：实验结果表明，LIPUS可通过降低AngII诱导的炎症细胞因子的释放，从而改善体内左室重构和体外心肌纤维化。但其对体外心肌肥大的保护作用有限。在机械刺激下，LIPUS能上调caveolin-1的表达。而进一步研究发现，在体内体外利用吡唑吡嘧啶2（pp2）预先抑制caveolin-1的活性后，LIPUS下调炎症反应和改善心肌纤维化的作用被明显逆转。以上结果表明，LIPUS可以通过caveolin-1依赖的途径减轻炎症，从而改善AngII诱导的心肌纤维化，并为这一新型治疗仪器的临床应用提供了新的思路和理论依据。
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DOI:
10.1631/jzus.B2100130
CLC number:
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On-line Access:
2021-10-12
Received:
2021-02-04
Revision Accepted:
2021-07-01
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