title: Advanced Interfere Treatment of Diabetic Cardiomyopathy Rats by aFGF-Loaded Heparin-Modified Microbubbles and UTMD Technique.
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.
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.|Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China.|Department of Pharmacy, Ningbo Yinzhou Second Hospital, Ningbo, Zhejiang, 315100, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Wen-Ze
authors.initials: WZ
authors.lastname: Yu
authors.affiliation: Department of Pharmacy, People's Hospital of Deqing County, Huzhou, Zhejiang, 313200, China.
authors.forename: Xiao-Tong
authors.initials: XT
authors.lastname: Shen
authors.affiliation: Biopharmaceutical R&D Center of Jinan University, Guangzhou, Guangdong, 510000, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Xiang
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Pian-Pian
authors.initials: PP
authors.lastname: Chen
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Zi-Liang
authors.initials: ZL
authors.lastname: Fan
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. xfxj2000@126.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Xiao
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. pharmtds@163.com.
authors.forename: Ying-Zheng
authors.initials: YZ
authors.lastname: Zhao
authors.affiliation: Department of Ultrasonography, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China. lctuua@sina.com.
authors.forename: Cui-Tao
authors.initials: CT
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D004452:Echocardiography; D016220:Fibroblast Growth Factor 1 / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006321:Heart / Q000000981:diagnostic imaging; D006493:Heparin / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D045423:Microbubbles; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D000069453:Ultrasonic Waves; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D007004:Hypoglycemic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D016220:Fibroblast Growth Factor 1; D006493:Heparin
keywords: AFGF; Diabetic cardiomyopathy; Heparin-modified bubble; Preventive strategy; Ultrasound-targeted microbubble destruction technique