Skip to main content
Top
Published in: BMC Cardiovascular Disorders 1/2021

Open Access 01-12-2021 | Ultrasound | Research article

Ultrasound-targeted microbubble destruction promotes myocardial angiogenesis and functional improvements in rat model of diabetic cardiomyopathy

Authors: Xijun Zhang, Xinqiao Tian, Peng Li, Haohui Zhu, Nanqian Zhou, Zhixin Fang, Yuping Yang, Yun Jing, Jianjun Yuan

Published in: BMC Cardiovascular Disorders | Issue 1/2021

Login to get access

Abstract

Background

Microvascular insufficiency plays an important role in the development of diabetic cardiomyopathy (DCM), therapeutic angiogenesis has been mainly used for the treatment of ischemic diseases. This study sought to verify the preclinical performance of SonoVue microbubbles (MB) combined ultrasound (US) treatment on myocardial angiogenesis in the rat model of DCM and investigate the optimal ultrasonic parameters.

Methods

The male Sprague–Dawley (SD) rats were induced DCM by streptozotocin through intraperitoneal injecting and fed with high-fat diet. After the DCM model was established, the rats were divided into the normal group, DCM model group, and US + MB group, while the US + MB group was divided into four subsets according to different pulse lengths (PL) (8 cycles;18 cycle;26 cycle; 36 cycle). After all interventions, all rats underwent conventional echocardiography to examine the cardiac function. The rats were sacrificed and myocardial tissue was examined by histology and morphometry evaluations to detect the myocardial protective effect of SonoVue MBs using US techniques.

Results

From morphologic observation and echocardiography, the DCM rats had a series of structural abnormalities of cardiac myocardium compared to the normal rats. The US-MB groups exerted cardioprotective effect in DCM rats, improved reparative neovascularization and increased cardiac perfusion, while the 26 cycle group showed significant therapeutic effects on the cardiac functions in DCM rats.

Conclusion

This strategy using SonoVue MB and US can improve the efficacy of angiogenesis, even reverse the progress of cardiac dysfunction and pathological abnormalities, especially using the 26 cycle parameters. Under further study, this combined strategy might provide a novel approach for early intervention of DCM in diabetic patients.
Literature
1.
go back to reference Mazzone T, Chait A, Plutzky J. Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet (London, England). 2008;371:1800–9.CrossRef Mazzone T, Chait A, Plutzky J. Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet (London, England). 2008;371:1800–9.CrossRef
2.
go back to reference Evangelista I, Nuti R, Picchioni T, Dotta F, Palazzuoli A. Molecular dysfunction and phenotypic derangement in diabetic cardiomyopathy. Int J Mol Sci. 2019;20:3264.CrossRef Evangelista I, Nuti R, Picchioni T, Dotta F, Palazzuoli A. Molecular dysfunction and phenotypic derangement in diabetic cardiomyopathy. Int J Mol Sci. 2019;20:3264.CrossRef
3.
go back to reference Gaurav SG, Athithan L, Gerry PM. Diabetic cardiomyopathy: prevalence, determinants and potential treatments. Ther Adv Endocrinol Metab. 2019;10:2042018819834869. Gaurav SG, Athithan L, Gerry PM. Diabetic cardiomyopathy: prevalence, determinants and potential treatments. Ther Adv Endocrinol Metab. 2019;10:2042018819834869.
4.
go back to reference Boodhwani M, Neel RS, Mieno S, Xu SH, Feng J, Ramlawi B, et al. Functional, cellular, and molecular characterization of the angiogenic response to chronic myocardial ischemia in diabetes. Circulation. 2007;116:I31–7.CrossRef Boodhwani M, Neel RS, Mieno S, Xu SH, Feng J, Ramlawi B, et al. Functional, cellular, and molecular characterization of the angiogenic response to chronic myocardial ischemia in diabetes. Circulation. 2007;116:I31–7.CrossRef
5.
go back to reference Zheng L, Shen CL, Li JM, Ma YL, Yan N, Tian XQ, et al. Assessment of the preventive effect against diabetic cardiomyopathy of FGF1-loaded nanoliposomes combined with microbubble cavitation by ultrasound. Front Pharmacol. 2019;10:1535.CrossRef Zheng L, Shen CL, Li JM, Ma YL, Yan N, Tian XQ, et al. Assessment of the preventive effect against diabetic cardiomyopathy of FGF1-loaded nanoliposomes combined with microbubble cavitation by ultrasound. Front Pharmacol. 2019;10:1535.CrossRef
6.
go back to reference Sara N, Edna S, João F, Sofia V, Eugénia C, Frederico CP, et al. Early cardiac changes in a rat model of prediabetes: brain natriuretic peptide overexpression seems to be the best marker. Cardiovasc Diabetol. 2013;12:44–44.CrossRef Sara N, Edna S, João F, Sofia V, Eugénia C, Frederico CP, et al. Early cardiac changes in a rat model of prediabetes: brain natriuretic peptide overexpression seems to be the best marker. Cardiovasc Diabetol. 2013;12:44–44.CrossRef
7.
go back to reference Sypalo A, Kravchun P, Kadykova O. The influence of mono- and multivascular lesions of coronary arteries on the course of coronary heart disease in patients with diabetes mellitus type 2. Georgian Med News. 2017;264:61–5. Sypalo A, Kravchun P, Kadykova O. The influence of mono- and multivascular lesions of coronary arteries on the course of coronary heart disease in patients with diabetes mellitus type 2. Georgian Med News. 2017;264:61–5.
8.
go back to reference Hinkel R, Howe A, Renner S, Ng J, Lee S, Klett K, et al. Diabetes mellitus-induced microvascular destabilization in the myocardium. J Am Coll Cardiol. 2017;69:131–43.CrossRef Hinkel R, Howe A, Renner S, Ng J, Lee S, Klett K, et al. Diabetes mellitus-induced microvascular destabilization in the myocardium. J Am Coll Cardiol. 2017;69:131–43.CrossRef
9.
go back to reference Singla D, Wang J. Fibroblast growth factor-9 activates c-Kit progenitor cells and enhances angiogenesis in the infarcted diabetic heart. Oxidative Med Cell Longev. 2016;2016:5810908.CrossRef Singla D, Wang J. Fibroblast growth factor-9 activates c-Kit progenitor cells and enhances angiogenesis in the infarcted diabetic heart. Oxidative Med Cell Longev. 2016;2016:5810908.CrossRef
10.
go back to reference Dai XZ, Yan XQ, Zeng J, Chen J, Wang YH, Chen J, et al. Elevating CXCR7 improves angiogenic function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 activation in diabetic limb ischemia. Circ Res. 2017;120:e7–23.CrossRef Dai XZ, Yan XQ, Zeng J, Chen J, Wang YH, Chen J, et al. Elevating CXCR7 improves angiogenic function of EPCs via Akt/GSK-3β/Fyn-Mediated Nrf2 activation in diabetic limb ischemia. Circ Res. 2017;120:e7–23.CrossRef
11.
go back to reference Teng X, Ji C, Zhong H, Zheng D, Ni R, Hill DJ, et al. Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis. Diabetologia. 2019;62:860–72.CrossRef Teng X, Ji C, Zhong H, Zheng D, Ni R, Hill DJ, et al. Selective deletion of endothelial cell calpain in mice reduces diabetic cardiomyopathy by improving angiogenesis. Diabetologia. 2019;62:860–72.CrossRef
12.
go back to reference Zhao YZ, Tian XQ, Zhang M, Cai L, Ru A, Shen XT, et al. Functional and pathological improvements of the hearts in diabetes model by the combined therapy of bFGF-loaded nanoparticles with ultrasound-targeted microbubble destruction. J Controll Release Off J Controll Release Soc. 2014;186:22–31.CrossRef Zhao YZ, Tian XQ, Zhang M, Cai L, Ru A, Shen XT, et al. Functional and pathological improvements of the hearts in diabetes model by the combined therapy of bFGF-loaded nanoparticles with ultrasound-targeted microbubble destruction. J Controll Release Off J Controll Release Soc. 2014;186:22–31.CrossRef
13.
go back to reference Zhao YZ, Zhang M, Ho LW, Tian XQ, Zheng L, Yu XC, et al. Prevent diabetic cardiomyopathy in diabetic rats by combined therapy of aFGF-loaded nanoparticles and ultrasound-targeted microbubble destruction technique. J Controll Release Off J Controll Release Soc. 2016;223:11–21.CrossRef Zhao YZ, Zhang M, Ho LW, Tian XQ, Zheng L, Yu XC, et al. Prevent diabetic cardiomyopathy in diabetic rats by combined therapy of aFGF-loaded nanoparticles and ultrasound-targeted microbubble destruction technique. J Controll Release Off J Controll Release Soc. 2016;223:11–21.CrossRef
14.
go back to reference Dietrich CF. Comments and illustrations regarding the guidelines and good clinical practice recommendations for contrast-enhanced ultrasound (CEUS)—update 2008. Ultraschall Med. 2008;29:S188–202.CrossRef Dietrich CF. Comments and illustrations regarding the guidelines and good clinical practice recommendations for contrast-enhanced ultrasound (CEUS)—update 2008. Ultraschall Med. 2008;29:S188–202.CrossRef
15.
go back to reference Dietrich CF, Nolsøe CP, Barr RG, Berzigotti A, Burns PN, Cantisani V, et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver-update 2020-WFUMB in cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultraschall Med. 2020;41:562–85.CrossRef Dietrich CF, Nolsøe CP, Barr RG, Berzigotti A, Burns PN, Cantisani V, et al. Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) in the liver-update 2020-WFUMB in cooperation with EFSUMB, AFSUMB, AIUM, and FLAUS. Ultraschall Med. 2020;41:562–85.CrossRef
16.
go back to reference Thomsen HS. European Society of Urogenital Radiology (ESUR) guidelines on the safe use of iodinated contrast media. Eur J Radiol. 2006;60:307–13.CrossRef Thomsen HS. European Society of Urogenital Radiology (ESUR) guidelines on the safe use of iodinated contrast media. Eur J Radiol. 2006;60:307–13.CrossRef
17.
go back to reference Wang XY, Pan JY, Liu H, Zhang MJ, Liu D, Lu L, et al. AIM2 gene silencing attenuates diabetic cardiomyopathy in type 2 diabetic rat model. Life Sci. 2019;221:249–58.CrossRef Wang XY, Pan JY, Liu H, Zhang MJ, Liu D, Lu L, et al. AIM2 gene silencing attenuates diabetic cardiomyopathy in type 2 diabetic rat model. Life Sci. 2019;221:249–58.CrossRef
18.
go back to reference Xue JT, Shi YL, Li CY, Xu XJ, Xu SX, Cao MX. Methylcellulose and polyacrylate binary hydrogels used as rectal suppository to prevent type I diabetes. Colloids Surf B Biointerfaces. 2018;172:37–42.CrossRef Xue JT, Shi YL, Li CY, Xu XJ, Xu SX, Cao MX. Methylcellulose and polyacrylate binary hydrogels used as rectal suppository to prevent type I diabetes. Colloids Surf B Biointerfaces. 2018;172:37–42.CrossRef
19.
go back to reference Zheng WC, Li D, Gao X, Zhang WQ, Barry OR. Carvedilol alleviates diabetic cardiomyopathy in diabetic rats. Exp Therap Med. 2019;17:479–87. Zheng WC, Li D, Gao X, Zhang WQ, Barry OR. Carvedilol alleviates diabetic cardiomyopathy in diabetic rats. Exp Therap Med. 2019;17:479–87.
20.
go back to reference Huang R, Shi ZD, Chen L, Zhang YQ, Li J, An Y. Rutin alleviates diabetic cardiomyopathy and improves cardiac function in diabetic ApoEknockout mice. Eur J Pharmacol. 2017;814:151–60.CrossRef Huang R, Shi ZD, Chen L, Zhang YQ, Li J, An Y. Rutin alleviates diabetic cardiomyopathy and improves cardiac function in diabetic ApoEknockout mice. Eur J Pharmacol. 2017;814:151–60.CrossRef
21.
go back to reference Hanawa K, Ito K, Aizawa K, Shindo T, Nishimiya K, Hasebe Y, et al. Low-intensity pulsed ultrasound induces angiogenesis and ameliorates left ventricular dysfunction in a porcine model of chronic myocardial ischemia. PLoS ONE. 2014;9:e104863.CrossRef Hanawa K, Ito K, Aizawa K, Shindo T, Nishimiya K, Hasebe Y, et al. Low-intensity pulsed ultrasound induces angiogenesis and ameliorates left ventricular dysfunction in a porcine model of chronic myocardial ischemia. PLoS ONE. 2014;9:e104863.CrossRef
22.
go back to reference Xue JT, Zhou NQ, Yang YP, Jing Y, Qiu Y, Liu YH, et al. Puerarin-loaded ultrasound microbubble contrast agent used as sonodynamic therapy for diabetic cardiomyopathy rats. Colloids Surf B Biointerfaces. 2020;190:110887.CrossRef Xue JT, Zhou NQ, Yang YP, Jing Y, Qiu Y, Liu YH, et al. Puerarin-loaded ultrasound microbubble contrast agent used as sonodynamic therapy for diabetic cardiomyopathy rats. Colloids Surf B Biointerfaces. 2020;190:110887.CrossRef
23.
go back to reference Tian XQ, Ni XW, Xu HL, Zheng L, ZhuGe DL, Chen B, et al. Prevention of doxorubicin-induced cardiomyopathy using targeted MaFGF mediated by nanoparticles combined with ultrasound-targeted MB destruction. Int J Nanomed. 2017;12:7103–19.CrossRef Tian XQ, Ni XW, Xu HL, Zheng L, ZhuGe DL, Chen B, et al. Prevention of doxorubicin-induced cardiomyopathy using targeted MaFGF mediated by nanoparticles combined with ultrasound-targeted MB destruction. Int J Nanomed. 2017;12:7103–19.CrossRef
24.
go back to reference Kawaguchi M, Techigawara M, Ishihata T, Asakura T, Saito F, Maehara K, et al. A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension. Heart Vessels. 1997;12:267–74.CrossRef Kawaguchi M, Techigawara M, Ishihata T, Asakura T, Saito F, Maehara K, et al. A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension. Heart Vessels. 1997;12:267–74.CrossRef
25.
go back to reference Todd BJ, Brian HM, Xie A, Zhao Y, Kim S, Nathan JL, et al. Augmentation of limb perfusion and reversal of tissue ischemia produced by ultrasound-mediated microbubble cavitation. Circ Cardiovasc Imaging. 2015;8:e002979. Todd BJ, Brian HM, Xie A, Zhao Y, Kim S, Nathan JL, et al. Augmentation of limb perfusion and reversal of tissue ischemia produced by ultrasound-mediated microbubble cavitation. Circ Cardiovasc Imaging. 2015;8:e002979.
26.
go back to reference Huang JJ, Shi YQ, Li RL, Hu A, Lu ZY, Weng L, et al. Angiogenesis effect of therapeutic ultrasound on HUVECs through activation of the PI3K-Akt-eNOS signal pathway. Am J Transl Res. 2015;7:1106–15.PubMedPubMedCentral Huang JJ, Shi YQ, Li RL, Hu A, Lu ZY, Weng L, et al. Angiogenesis effect of therapeutic ultrasound on HUVECs through activation of the PI3K-Akt-eNOS signal pathway. Am J Transl Res. 2015;7:1106–15.PubMedPubMedCentral
27.
go back to reference Zhang M, Yu WZ, Shen XT, Xiang Q, Xu J, Yang JJ, et al. Advanced interfere treatment of diabetic cardiomyopathy rats by aFGF-loaded heparin-modified microbubbles and UTMD technique. Cardiovasc Drugs Ther. 2016;30:247–61.CrossRef Zhang M, Yu WZ, Shen XT, Xiang Q, Xu J, Yang JJ, et al. Advanced interfere treatment of diabetic cardiomyopathy rats by aFGF-loaded heparin-modified microbubbles and UTMD technique. Cardiovasc Drugs Ther. 2016;30:247–61.CrossRef
28.
go back to reference Chen YP, Ba LN, Huang W, Liu Y, Pan H, Mingyao E, et al. Role of carvacrol in cardioprotection against myocardial ischemia/reperfusion injury in rats through activation of MAPK/ERK and Akt/eNOS signaling pathways. Eur J Pharmacol. 2017;796:90–100.CrossRef Chen YP, Ba LN, Huang W, Liu Y, Pan H, Mingyao E, et al. Role of carvacrol in cardioprotection against myocardial ischemia/reperfusion injury in rats through activation of MAPK/ERK and Akt/eNOS signaling pathways. Eur J Pharmacol. 2017;796:90–100.CrossRef
29.
go back to reference Xu H, Xu H, Hai GF, Qing HE, Zhang C. Protective effect of modified human acidic fibroblast growth factor against actinomycin D-induced NRK52E cells apoptotic death. Trop J Pharm Res. 2013;12:343–9. Xu H, Xu H, Hai GF, Qing HE, Zhang C. Protective effect of modified human acidic fibroblast growth factor against actinomycin D-induced NRK52E cells apoptotic death. Trop J Pharm Res. 2013;12:343–9.
Metadata
Title
Ultrasound-targeted microbubble destruction promotes myocardial angiogenesis and functional improvements in rat model of diabetic cardiomyopathy
Authors
Xijun Zhang
Xinqiao Tian
Peng Li
Haohui Zhu
Nanqian Zhou
Zhixin Fang
Yuping Yang
Yun Jing
Jianjun Yuan
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Cardiovascular Disorders / Issue 1/2021
Electronic ISSN: 1471-2261
DOI
https://doi.org/10.1186/s12872-020-01815-4

Other articles of this Issue 1/2021

BMC Cardiovascular Disorders 1/2021 Go to the issue