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Hydrogen sulfide‐loaded microbubbles combined with ultrasound mediate thrombolysis and simultaneously mitigate ischemia‐reperfusion injury in a rat hindlimb model
Author(s) -
Zhong Jiayuan,
Sun Yili,
Han Yuan,
Chen Xiaoqiang,
Li Hairui,
Ma Yusheng,
Lai Yanxian,
Wei Guoquan,
He Xiang,
Li Mengsha,
Liao Wangjun,
Liao Yulin,
Cao Shiping,
Bin Jianping
Publication year - 2021
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.15110
Subject(s) - ex vivo , in vivo , skeletal muscle , hindlimb , thrombolysis , microbubbles , reperfusion injury , ischemia , medicine , perfusion , apoptosis , chemistry , pharmacology , ultrasound , biology , myocardial infarction , biochemistry , microbiology and biotechnology , radiology
Background Thromboembolism and subsequent ischemia/reperfusion injury (IRI) remain major clinical challenges. Objectives To investigate whether hydrogen sulfide (H 2 S)‐loaded microbubbles (hs‐Mbs) combined with ultrasound (US) radiation (hs‐Mbs+US) dissolve thrombi and simultaneously alleviate tissue IRI through local H 2 S release. Methods hs‐Mbs were manufactured and US‐triggered H 2 S release was recorded. White and red thromboembolisms were established ex vivo and in rats left iliac artery. All subjects randomly received control, US, Mbs+US, or hs‐Mbs+US treatment for 30 minutes. Results H 2 S was released from hs‐Mbs+US both ex vivo and in vivo. Compared with control and US, hs‐Mbs+US and Mbs+US showed comparable substantial decreases in thrombotic area, clot mass, and flow velocity increases for both ex vivo macrothrombi. In vivo, hs‐Mbs+US and Mbs+US caused similarly increased recanalization rates, blood flow velocities, and hindlimb perfusion for both thrombi compared with the other treatments, with no obvious influence on hemodynamics, respiration, and macrophage vitality. More importantly, hs‐Mbs+US substantially alleviated skeletal muscle IRI by reducing reactive oxygen species, cellular apoptosis, and proapoptotic Bax, caspase‐3, and caspase‐9 and increasing antiapoptotic Bcl‐2 compared with other treatments. In vitro, hypoxia/reoxygenation‐predisposed skeletal muscle cells and endothelial cells treated with normal saline solution exhibited similar trends, which were largely reversed by an H 2 S scavenger or an inhibitor of Akt phosphorylation. Conclusion hs‐Mbs+US effectively dissolved both white and red macrothrombi and simultaneously alleviated skeletal muscle IRI through the US‐triggered, organ‐specific release of H 2 S. This integrated therapeutic strategy holds promise for treating thromboembolic diseases and subsequent IRI.