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Advanced Interfere Treatment of Diabetic Cardiomyopathy Rats by aFGF-Loaded Heparin-Modified Microbubbles and UTMD Technique

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Abstract

This study aims to investigate the preclinical performance and mechanism of a novel strategy of aFGF-loaded heparin-modified microbubbles (aFGF-HMB) combined with ultrasound-targeted microbubble destruction (UTMD) technique for diabetic cardiomyopathy (DCM) prevention. Type 1 diabetic rats were induced by streptozotocin. Twelve weeks after intervention, indexes from transthoracic echocardiography and cardiac catheterization showed that the left ventricular function in the aFGF-HMB/UTMD group was significantly improved compared with diabetes control (DM). From Picrosirius Red staining and TUNEL staining, the aFGF-HMB/UTMD group showed significant difference from the other groups. The cardiac collagen volume fraction (CVF) and myocardial cell apoptosis index (AI) in aFGF-HMB/UTMD group decreased to 7.2 % and 7.11 % respectively, compared with the DM group (CVF = 24.5 % and AI =20.3 % respectively). The results of myocardial microvascular density (MCD) also proved the strongest inhibition of aFGF-HMB/UTMD group on DCM progress. CD31 staining of aFGF-HMB/UTMD group reached 22 n/hrp, much higher than that of DM group (9 n/hrp). These results confirmed that the abnormalities including left ventricular dysfunction, myocardial fibrosis, cardiomyocytes apoptosis and microvascular rarefaction could be suppressed by twice weekly aFGF treatments for 12 consecutive weeks (free aFGF or aFGF-HMB+/−UTMD), with the strongest improvements observed in the aFGF-HMB/UTMD group (P < 0.05 vs free aFGF or aFGF-HMB). Western blot analyses of heart tissue further revealed the highest aFGF, anti-apoptosis protein (Bcl-2), VEGF-C, pAkt, pFoxo-3a levels and strongest reduction in pro-apoptosis proteins (Bax) level in aFGF-HMB/UTMD group. Overall, aFGF-HMB combined with UTMD technique might be developed as an effective strategy to prevent DCM in future clinical therapy.

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Abbreviations

DM:

Diabetes

DCM:

Diabetic cardiomyopathy

MB:

Microbubbles

HMB:

Heparin-modified microbubbles

aFGF or FGF-1:

acid fibroblast growth factor

bFGF:

basic fibroblast growth factor

aFGF-HMB:

aFGF-loaded heparin-modified microbubbles

UTMD:

Ultrasound-targeted microbubble destruction

aFGF-HMB/UTMD:

aFGF-loaded heparin-modified Microbubbles combined with ultrasound- targeted microbubble destruction

CVF:

Collagen volume fraction

AI:

Apoptosis index

MCD:

Myocardial capillary density

QDs:

Quantum dots

LVEF:

Left ventricle ejection fraction

LVFS:

Left ventricle fractional shortening

Vs:

Peak systolic radial velocity

Sc:

Systolic circumferential strain

SRc:

Systolic circumferential strain rate

Sr:

Systolic radial strain

SRr:

Systolic radial strain rate

LV:

Left ventricle

LVESP:

Left ventricle end-systolic pressure

LVEDP:

end-diastolic pressure

±dp/dt max:

The maximum rising and dropping rates of left ventricle pressure

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Acknowledgments

This research was supported by National Natural Science Foundation of China (Grant No. 81301982, 81360195, 81571392 and 81272160). Zhejiang Provincial Foundation for Health Department (Grant No. 2015ZDA023). Key support of high level talent innovation and technology project of Wenzhou (Zhao Ying-Zheng, 2015). Major Scientific Project of Guangdong Province (Grant No. 2012 A080201010). Science and Technology Program of Guangzhou, China (201508020001).

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  1. Jian Xiao

    Present address: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

Authors and Affiliations

  1. College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Ming Zhang, Wen-Ze Yu, Jie Xu, Jing-Jing Yang, Pian-Pian Chen, Zi-Liang Fan & Ying-Zheng Zhao

  2. Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China

    Ming Zhang & Cui-Tao Lu

  3. Department of Pharmacy, Ningbo Yinzhou Second Hospital, Ningbo, Zhejiang, 315100, China

    Ming Zhang

  4. Department of Pharmacy, People’s Hospital of Deqing County, Huzhou, Zhejiang, 313200, China

    Xiao-Tong Shen

  5. Biopharmaceutical R&D Center of Jinan University, Guangzhou, Guangdong, 510000, China

    Qi Xiang

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Correspondence to Jian Xiao, Ying-Zheng Zhao or Cui-Tao Lu.

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Ming Zhang, Wen-Ze Yu and Xiao-Tong Shen contributed equally to this work.

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Zhang, M., Yu, WZ., Shen, XT. et al. Advanced Interfere Treatment of Diabetic Cardiomyopathy Rats by aFGF-Loaded Heparin-Modified Microbubbles and UTMD Technique. Cardiovasc Drugs Ther 30, 247–261 (2016). https://doi.org/10.1007/s10557-016-6639-4

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