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Hypoxia‐induced cardiac fibrosis is an important pathological process in cardiovascular disorders. This study aimed to determine whether low‐intensity pulsed ultrasound (LIPUS), a novel and safe apparatus, could alleviate hypoxia‐induced cardiac fibrosis, and to elucidate the underlying mechanisms. Hypoxia (1% O2) and transverse aortic constriction (TAC) were performed on neonatal rat cardiac fibroblasts and mice to induce cardiac fibrosis, respectively. LIPUS irradiation was applied for 20 minutes every 6 hours for a total of 2 times in vitro, and every 2 days from 1 week before surgery to 4 weeks after surgery in vivo. We found that LIPUS dose‐dependently attenuated hypoxia‐induced cardiac fibroblast phenotypic conversion in vitro, and ameliorated TAC‐induced cardiac fibrosis in vivo. Hypoxia significantly upregulated the nuclear protein expression of hypoxia‐inducible factor‐1α (HIF‐1α) and DNA methyltransferase 3a (DNMT3a). LIPUS pre‐treatment reversed the elevated expression of HIF‐1α, and DNMT3a. Further experiments revealed that HIF‐1α stabilizer dimethyloxalylglycine (DMOG) hindered the anti‐fibrotic effect of LIPUS, and hampered LIPUS‐mediated downregulation of DNMT3a. DNMT3a small interfering RNA (siRNA) prevented hypoxia‐induced cardiac fibrosis. Results also showed that the mechanosensitive protein‐TWIK‐related arachidonic acid‐activated K+ channel (TRAAK) messenger RNA (mRNA) expression was downregulated in hypoxia‐induced cardiac fibroblasts, and TAC‐induced hearts. TRAAK siRNA impeded LIPUS‐mediated anti‐fibrotic effect and downregulation of HIF‐1α and DNMT3a. Above results indicated that LIPUS could prevent prolonged hypoxia‐induced cardiac fibrosis through TRAAK‐mediated HIF‐1α/DNMT3a signalling pathway. [ABSTRACT FROM AUTHOR]

Vascular events can trigger a pathological phenotypic switch in vascular smooth muscle cells (VSMCs), decreasing and disrupting the plasticity and diversity of vascular networks. The development of novel therapeutic approaches is necessary to prevent these changes. We aimed to investigate the effects and associated mechanisms of low-intensity pulsed ultrasound (LIPUS) irradiation on the angiotensin II (AngII)-induced phenotypic switch in VSMCs. In vivo , AngII was infused subcutaneously for 4 weeks to stimulate vascular remodeling in mice, and LIPUS irradiation was applied for 20 min every 2 days for 4 weeks. In vitro , cultured rat aortic VSMCs (RAVSMCs) were pretreated once with LIPUS irradiation for 20 min before 48-h AngII stimulation. Our results showed that LIPUS irradiation prevents AngII-induced vascular remodeling of the whole wall artery without discriminating between adventitia and media in vivo and RAVSMC phenotypic switching in vitro. LIPUS irradiation downregulated miR-17-5p expression and upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) expression. The PPAR-γ activator rosiglitazone could mimic the favorable effects of LIPUS irradiation on AngII-treated RAVSMCs. In contrast, GW9662 could impede the LIPUS-mediated downregulation of RAVSMC proliferation and inflammation under AngII stimulation conditions in vivo and in vitro. Also, the miR-17-5p agomir has the same effects as GW9662 in vitro. Besides, the inhibitory effects of GW9662 against the anti-remodeling effects of LIPUS irradiation in AngII-induced RAVSMCs could be blocked by pretreatment with the miR-17-5p antagomir. Overall, LIPUS irradiation prevents AngII-induced RAVSMCs phenotypic switching through hampering miR-17-5p and enhancing PPAR-γ, suggesting a new approach for the treatment of vascular disorders. [Display omitted] • LIPUS irradiation ameliorates AngII-induced vascular remodeling in vivo. • LIPUS irradiation ameliorates AngII-induced RASMCs phenotypic switch in vitro. • LIPUS irradiation exerts its vascular protective effects via hampering miR-17-5p. • LIPUS irradiation exerts its vascular protective effects via enhancing PPAR-γ. • We provided a novel and safe approach for the treatment of vascular disorders. [ABSTRACT FROM AUTHOR]