Non-Invasive Local Acoustic Therapy Ameliorates Diabetic Heart Fibrosis by Suppressing ACE-Mediated Oxidative Stress and Inflammation in Cardiac Fibroblasts

Weng, Liqing; Lu, Li; Zhao, Kun; Xu, Tianhua; Mao, Yu; Shu, Huanyu; Chen, Xuguan; Chen, Ji; Wu, Jian; Guo, Xiasheng; Tu, Juan; Zhang, Dong; Sun, Wei; Kong, Xiangqing

doi:10.1007/s10557-021-07297-6

Cited by 5 publications

(5 citation statements)

References 36 publications

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“…As a safe and non‐invasive approach, LIPUS has shown great potential in tissue repair and resolution of inflammation in various diseases 32–35 . Of note, the therapeutic effects of LIPUS on cardiovascular diseases have been reported in recent years 10–14 . In our present study, we showed that LIPUS therapy provided a great benefit in both acute and chronic DOX injury models, including the improvement of cardiac contractile function, the attenuation of myocardial injury and cellular apoptosis, as well as the alleviation of oxidative stress and cardiac fibrosis.…”

Section: Discussionsupporting

confidence: 59%

“…8 Through changing micromechanical stress in local tissues, LIPUS causes a series of biological reactions to accelerate the repair process of tissue injuries. 8,9 Notably, LIPUS has shown great therapeutic potential in cardiovascular diseases such as myocardial infarction, 10 cardiac fibrosis, 11,12 viral myocarditis, 13 and heart failure with preserved left ventricular ejection fraction. 14 The molecular mechanisms of LIPUS therapy mainly involve regulations of oxidative stress, 12 inflammation [11][12][13] and endothelial function.…”

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confidence: 99%

“…8,9 Notably, LIPUS has shown great therapeutic potential in cardiovascular diseases such as myocardial infarction, 10 cardiac fibrosis, 11,12 viral myocarditis, 13 and heart failure with preserved left ventricular ejection fraction. 14 The molecular mechanisms of LIPUS therapy mainly involve regulations of oxidative stress, 12 inflammation [11][12][13] and endothelial function. 10,14 Interestingly, a recent study has demonstrated that brief exposure to LIPUS was sufficient to eliminate paclitaxel treatment-induced cytotoxicity, and might provide a new strategy to counter chemotherapyinduced peripheral neuropathy and alopecia.…”

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confidence: 99%

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Low‐intensity pulsed ultrasound alleviates doxorubicin‐induced cardiotoxicity via inhibition of S100a8/a9‐mediated cardiac recruitment of neutrophils

Zhu

Wang

et al. 2023

Bioengineering & Transla Med

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Doxorubicin (DOX)‐induced cardiotoxicity limits its broad use as a chemotherapy agent. The development of effective and non‐invasive strategies to prevent DOX‐associated adverse cardiac events is urgently needed. We aimed to examine whether and how low‐intensity pulsed ultrasound (LIPUS) plays a protective role in DOX‐induced cardiotoxicity. Male C57BL/6J mice were used to establish models of both acute and chronic DOX‐induced cardiomyopathy. Non‐invasive LIPUS therapy was conducted for four consecutive days after DOX administration. Cardiac contractile function was evaluated by echocardiography. Myocardial apoptosis, oxidative stress, and fibrosis were analyzed using terminal deoxynucleotidyl transferase‐mediated dUTP nick end labelling (TUNEL) staining, dihydroethidium (DHE) staining, and picrosirius red staining assays. RNA‐seq analysis was performed to unbiasedly explore the possible downstream regulatory mechanisms. Neutrophil recruitment and infiltration in the heart were analyzed by flow cytometry. The S100a8/a9 inhibitor ABR‐238901 was utilized to identify the effect of S100a8/a9 signaling. We found that LIPUS therapy elicited a great benefit on DOX‐induced heart contractile dysfunction in both acute and chronic DOX models. Chronic DOX administration increased serum creatine kinase and lactate dehydrogenase levels, as well as myocardial apoptosis, all of which were significantly mitigated by LIPUS. In addition, LIPUS treatment prevented chronic DOX‐induced cardiac oxidative stress and fibrosis. RNA‐seq analysis revealed that LIPUS treatment partially reversed alterations of gene expression induced by DOX. Gene ontology (GO) analysis of the downregulated genes between DOX‐LIPUS and DOX‐Sham groups indicated that inhibition of neutrophil chemotaxis might be involved in the protective effects of LIPUS therapy. Flow cytometry analysis illustrated the inhibitory effects of LIPUS on DOX‐induced neutrophil recruitment and infiltration in the heart. Moreover, S100 calcium binding protein A8/A9 (S100a8/a9) was identified as a potential key target of LIPUS therapy. S100a8/a9 inhibition by ABR‐238901 showed a similar heart protective effect against DOX‐induced cardiomyopathy to LIPUS treatment. LIPUS therapy prevents DOX‐induced cardiotoxicity through inhibition of S100a8/a9‐mediated neutrophil recruitment to the heart, suggesting its potential application in cancer patients undergoing chemotherapy with DOX.

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Section: Discussionsupporting

confidence: 59%

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confidence: 99%

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confidence: 99%

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Low‐intensity pulsed ultrasound alleviates doxorubicin‐induced cardiotoxicity via inhibition of S100a8/a9‐mediated cardiac recruitment of neutrophils

Zhu

Wang

et al. 2023

Bioengineering & Transla Med

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“…4.5 LIPUS of 0.5 W/cm 2 exerts cardioprotective effects by downregulating ASK1/JNK pathway under the hypoxic conditions MI/R injury involves intricate signalings, including ROS signaling, which is particularly over-activated during reperfusion (43,46,56). LIPUS has been demonstrated to reduce cell injury by protecting against oxidative stress in several cardiovascular diseases (20)(21)(22). Therefore, we further attempt to clarify whether LIPUS protects against MI/R injury by regulating ROS signaling.…”

Section: Different Intensities Of Lipus Exert Different Effects On Ca...mentioning

confidence: 99%

“…In recent years, few researches have studied the effects of LIPUS on different disease models with ischemia/reperfusion injury in which LIPUS has been proven to protect against cerebral ischemia/reperfusion injury and prevent recurrent ischemic stroke in the cerebral ischemia/reperfusion injury mouse model via apoptosis reduction ( 18 , 19 ). Furthermore, LIPUS has been demonstrated to reduce cell injury by inhibiting inflammatory reaction and oxidative stress in many diseases, including cardiovascular diseases, but rarely on MI/R injury ( 20 – 22 ). Our previous study has demonstrated that LIPUS can promote cell viability and inhibits apoptosis of H9C2 cardiomyocytes in 3D bioprinting scaffolds ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

Low-intensity pulsed ultrasound of different intensities differently affects myocardial ischemia/reperfusion injury by modulating cardiac oxidative stress and inflammatory reaction

Cao,

Liu,

et al. 2023

Front. Immunol.

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IntroductionThe prevalence of ischemic heart disease has reached pandemic levels worldwide. Early revascularization is currently the most effective therapy for ischemic heart diseases but paradoxically induces myocardial ischemia/reperfusion (MI/R) injury. Cardiac inflammatory reaction and oxidative stress are primarily involved in the pathology of MI/R injury. Low-intensity pulsed ultrasound (LIPUS) has been demonstrated to reduce cell injury by protecting against inflammatory reaction and oxidative stress in many diseases, including cardiovascular diseases, but rarely on MI/R injury.MethodsThis study was designed to clarify whether LIPUS alleviates MI/R injury by alleviating inflammatory reaction and oxidative stress. Simultaneously, we have also tried to confirm which intensity of the LIPUS might be more suitable to ameliorate the MI/R injury, as well as to clarify the signaling mechanisms. MI/R and simulated ischemia/reperfusion (SI/R) were respectively induced in Sprague Dawley rats and human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). LIPUS treatment, biochemical measurements, cell death assay, estimation of cardiac oxidative stress and inflammatory reaction, and protein detections by western blotting were performed according to the protocol.ResultsIn our study, both in vivo and in vitro, LIPUS of 0.1 W/cm2 (LIPUS0.1) and 0.5 W/cm2 (LIPUS0.5) make no significant difference in the cardiomyocytes under normoxic condition. Under the hypoxic condition, MI/R injury, inflammatory reaction, and oxidative stress were partially ameliorated by LIPUS0.5 but were significantly aggravated by LIPUS of 2.5 W/cm2 (LIPUS2.5) both in vivo and in vitro. The activation of the apoptosis signal-regulating kinase 1 (ASK1)/c-Jun N-terminal kinase (JNK) pathway in cardiomyocytes with MI/R injury was partly rectified LIPUS0.5 both in vivo and in vitro.ConclusionOur study firstly demonstrated that LIPUS of different intensities differently affects MI/R injury by regulating cardiac inflammatory reaction and oxidative stress. Modulations on the ASK1/JNK pathway are the signaling mechanism by which LIPUS0.5 exerts cardioprotective effects. LIPUS0.5 is promising for clinical translation in protecting against MI/R injury. This will be great welfare for patients suffering from MI/R injury.

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Protective effect of low‐intensity pulsed ultrasound on immune checkpoint inhibitor-related myocarditis via fine-tuning CD4+ T-cell differentiation

Fu,

Guo,

et al. 2024

Cancer Immunol Immunother

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Purpose Immune checkpoint inhibitors (ICIs) have transformed traditional cancer treatments. Specifically, ICI-related myocarditis is an immune-related adverse event (irAE) with high mortality. ICIs activate CD4+ T-lymphocyte reprogramming, causing an imbalance between Th17 and Treg cell differentiation, ultimately leading to myocardial inflammatory damage. Low-intensity pulsed ultrasound (LIPUS) can limit inflammatory responses, with positive therapeutic effects across various cardiovascular inflammatory diseases; however, its role in the pathogenesis of ICI-related myocarditis and CD4+ T-cell dysfunction remains unclear. Accordingly, this study investigated whether LIPUS can alleviate ICI-related myocarditis inflammatory damage and, if so, aimed to elucidate the beneficial effects of LIPUS and its underlying molecular mechanisms. Methods An in vivo model of ICI-related myocarditis was obtained by intraperitonially injecting male A/J mice with an InVivoPlus anti-mouse PD-1 inhibitor. LIPUS treatment was performed via an ultrasound-guided application to the heart via the chest wall. The echocardiographic parameters were observed and cardiac function was assessed using an in vivo imaging system. The expression of core components of the HIPPO pathway was analyzed via western blotting. Results LIPUS treatment reduced cardiac immune responses and inflammatory cardiac injury. Further, LIPUS treatment alleviated the inflammatory response in mice with ICI-related myocarditis. Mechanistically, in the HIPPO pathway, the activation of Mst1–TAZ axis improved autoimmune inflammation by altering the interaction between the transcription factors FOXP3 and RORγt and regulating the differentiation of Treg and Th17 cells. Conclusion LIPUS therapy was shown to reduce ICI-related myocarditis inflammatory damage and improve cardiac function, representing an exciting finding for irAEs treatment.

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Non-Invasive Local Acoustic Therapy Ameliorates Diabetic Heart Fibrosis by Suppressing ACE-Mediated Oxidative Stress and Inflammation in Cardiac Fibroblasts

Cited by 5 publications

References 36 publications

Low‐intensity pulsed ultrasound alleviates doxorubicin‐induced cardiotoxicity via inhibition of S100a8/a9‐mediated cardiac recruitment of neutrophils

Low‐intensity pulsed ultrasound alleviates doxorubicin‐induced cardiotoxicity via inhibition of S100a8/a9‐mediated cardiac recruitment of neutrophils

Low-intensity pulsed ultrasound of different intensities differently affects myocardial ischemia/reperfusion injury by modulating cardiac oxidative stress and inflammatory reaction

Protective effect of low‐intensity pulsed ultrasound on immune checkpoint inhibitor-related myocarditis via fine-tuning CD4+ T-cell differentiation

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