PMID- 35082664 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220128 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 12 DP - 2021 TI - Ultrasound-Induced Destruction of Nitric Oxide-Loaded Microbubbles in the Treatment of Thrombus and Ischemia-Reperfusion Injury. PG - 745693 LID - 10.3389/fphar.2021.745693 [doi] LID - 745693 AB - Objectives: Early recanalization of large vessels in thromboembolism, such as myocardial infarction and ischemic stroke, is associated with improved clinical outcomes. Nitric oxide (NO), a biological gas signaling molecule, has been proven to protect against ischemia-reperfusion injury (IRI). However, the underlying mechanisms remain to be explored. This study investigated whether NO could mitigate IRI and the role of NO during acoustic cavitation. Methods: In vivo, thrombi in the iliac artery of rats were induced by 5% FeCl(3). NO-loaded microbubbles (NO-MBs) and ultrasound (US) were used to treat thrombi. B-mode and Doppler US and histological analyses were utilized to evaluate the thrombolysis effect in rats with thrombi. Immunohistochemistry, immunofluorescence, and western blotting were conducted to investigate the underlying mechanisms of NO during acoustic cavitation. In vitro, hypoxia was used to stimulate cells, and NO-MBs were employed to alleviate oxidative stress and apoptosis. Results: We developed NO-MBs that significantly improve the circulation time of NO in vivo, are visible, and effectively release therapeutic gas under US. US-targeted microbubble destruction (UTMD) and NO-loaded UTMD (NO + UTMD) caused a significant decrease in the thrombus area and an increase in the recanalization rates and blood flow velocities compared to the control and US groups. We discovered that UTMD induced NO generation through activation of endothelial NO synthase (eNOS) in vivo. More importantly, we also observed significantly increased NO content and eNOS expression in the NO + UTMD group compared to the UTMD group. NO + UTMD can mitigate oxidative stress and apoptosis in the hind limb muscle without influencing blood pressure or liver and kidney functions. In vitro, NO-MBs alleviated oxidative stress and apoptosis in cells pretreated with hypoxia. Conclusion: Based on these data, UTMD affects the vascular endothelium by activating eNOS, and NO exerts a protective effect against IRI. CI - Copyright (c) 2022 Liang, Chen, Gong, Shi, Lin, Tao, Wu, Fang, Li, Lu, Xu, Zhao and Chen. FAU - Liang, Zenghui AU - Liang Z AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Chen, Huafang AU - Chen H AD - The Office of Drug Clinical Trial Institution, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Gong, Xuehao AU - Gong X AD - Department of Ultrasound, First Affiliated Hospital of Shenzhen University, Second People's Hospital of Shenzhen, Shenzhen, China. FAU - Shi, Binbin AU - Shi B AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Lin, Lili AU - Lin L AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Tao, Fangyi AU - Tao F AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Wu, Qilong AU - Wu Q AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Fang, Mingling AU - Fang M AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Li, Hui AU - Li H AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. FAU - Lu, Cuitao AU - Lu C AD - Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China. FAU - Xu, Helin AU - Xu H AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. AD - Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China. FAU - Zhao, Yingzheng AU - Zhao Y AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. AD - Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China. FAU - Chen, Bin AU - Chen B AD - Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. AD - Department of Ultrasound, First Affiliated Hospital of Shenzhen University, Second People's Hospital of Shenzhen, Shenzhen, China. LA - eng PT - Journal Article DEP - 20220104 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC8785684 OTO - NOTNLM OT - endothelial nitric oxide synthase OT - ischemia-reperfusion injury OT - nitric oxide OT - thrombus OT - ultrasound-targeted microbubbles destruction COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2022/01/28 06:00 MHDA- 2022/01/28 06:01 PMCR- 2022/01/04 CRDT- 2022/01/27 05:48 PHST- 2021/07/22 00:00 [received] PHST- 2021/11/17 00:00 [accepted] PHST- 2022/01/27 05:48 [entrez] PHST- 2022/01/28 06:00 [pubmed] PHST- 2022/01/28 06:01 [medline] PHST- 2022/01/04 00:00 [pmc-release] AID - 745693 [pii] AID - 10.3389/fphar.2021.745693 [doi] PST - epublish SO - Front Pharmacol. 2022 Jan 4;12:745693. doi: 10.3389/fphar.2021.745693. eCollection 2021.