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Low-intensity pulsed ultrasound ameliorates angiotensin II-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway

低强度脉冲超声(LIPUS)通过小窝蛋白-1(caveolin-1)依赖性途径减轻炎症, 从而改善血管紧张素II(AngII)诱导的心脏纤维化

Abstract

Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

Abstract

目的

心肌肥厚和纤维化是血管紧张素II(AngII)引起的左心室重构的主要病理表现. 既往研究表明低强度脉冲超声(LIPUS)能通过机械传导及其下游途径改善心肌梗死(MI)患者的心功能不全和心肌纤维化. 因此, 本研究旨在探讨LIPUS是否能改善AngII诱导的心肌肥厚和纤维化, 并进一步阐明其潜在分子机制.

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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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81627802), the Priority Academic Program Development of Jiangsu Higher Education Institutions (No. PAPD2014-2016), and the National Key R&D Program of China (No. 2019YFA0210100).

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Correspondence to Bin Zhou or Wei Sun.

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Author contributions

Kun ZHAO performed the experimental research and contributed to the study design, wrote and edited the manuscript. Jing ZHANG performed the establishment of animal models, wrote and edited the manuscript. Tianhua XU contributed to the study design. Chuanxi YANG and Xiaoguang WU contributed to the data analysis. Liqing WENG and Tingting WU contributed to the establishment of animal models. Jiaming MIAO, Xiasheng GUO, Juan TU, Dong ZHANG, and Xiangqing KONG contributed to the design and build of LIPUS. Bin ZHOU, Wei SUN, and Xiangqing KONG edited the manuscript. All authors have read and approved the final manuscript and, therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.

Compliance with ethics guidelines

Kun ZHAO, Jing ZHANG, Tianhua XU, Chuanxi YANG, Liqing WENG, Tingting WU, Xiaoguang WU, Jiaming MIAO, Xiasheng GUO, Juan TU, Dong ZHANG, Bin ZHOU, Wei SUN, and Xiangqing KONG declare that they have no conflict of interest.

All experiments with animals were conducted strictly following the University’s guidelines for the Care and Use of Laboratory Animals (Publication No. 85-23, Revised 1996; National Institutes of Health, Bethesda, MD, USA) and were approved by the Committee on Use and Care of Experimental Animals of Nanjing Medical University (Nanjing, China).

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Zhao, K., Zhang, J., Xu, T. et al. Low-intensity pulsed ultrasound ameliorates angiotensin II-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway. J. Zhejiang Univ. Sci. B 22, 818–838 (2021). https://doi.org/10.1631/jzus.B2100130

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Key words

  • Low-intensity pulsed ultrasound (LIPUS)
  • Caveolin-1
  • Cardiac fibrosis
  • Inflammation
  • Angiotensin II (AngII)

关键词

  • 低强度脉冲超声(LIPUS)
  • 小窝蛋白-1(caveolin-1)
  • 心脏纤维化
  • 炎症
  • 血管紧张素II(AngII)