title: Prevent diabetic cardiomyopathy in diabetic rats by combined therapy of aFGF-loaded nanoparticles and ultrasound-targeted microbubble destruction technique.
abstract: Acidic fibroblast growth factor (aFGF) has shown the great potential to prevent the structural and functional injuries caused by diabetic cardiomyopathy (DCM). The present study sought to investigate the preclinical performance and mechanism of the combination therapy of aFGF-nanoparticles (aFGF-NP) and ultrasound-targeted microbubble destruction (UTMD) technique for DCM prevention. From Mason staining and TUNEL staining, aFGF-NP+UTMD group showed significant differences from the diabetes group and other groups treated with aFGF or aFGF-NP. The cardiac collagen volume fraction (CVF) and cardiac myocyte apoptosis index in aFGF-NP+UTMD group reduced to 4.15% and 2.31% respectively, compared with those in the diabetes group (20.5% and 11.3% respectively). Myocardial microvascular density (MCD) in aFGF-NP+UTMD group was up to 35n/hpf, much higher than that in the diabetes group (14n/hpf). The diabetes group showed similar results (MCD, CVF and cardiac myocyte apoptosis index) to other aFGF treatment groups (free aFGF±UTMD or aFGF-NP). Indexes from transthoracic echocardiography and hemodynamic evaluation also proved the same conclusion. These results confirmed that the abnormalities including diastolic dysfunctions, myocardial fibrosis and metabolic could be suppressed by the different extents of twice weekly aFGF treatments for 12 consecutive weeks (free aFGF or aFGF-NP±UTMD), with the strongest improvements observed in the aFGF-NP+UTMD group. Western blot and immunohistochemical analyses of heart tissue samples further revealed the high efficiency of heart-targeted delivery and effective cardioprotection with this combination approach. Overall, this study has generated supportive data that are critical for the translation of a promising DCM prevention strategy.
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
authors.forename: Ying-Zheng
authors.initials: YZ
authors.lastname: Zhao
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Ho Lun
authors.initials: HL
authors.lastname: Wong
authors.affiliation: Department of Ultrasonography, Henan Provincial People's Hospital (People's Hospital of Zhengzhou University), Zhengzhou, Henan 450003, China.
authors.forename: Xin-Qiao
authors.initials: XQ
authors.lastname: Tian
authors.affiliation: Department of Ultrasonography, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Xi-Chong
authors.initials: XC
authors.lastname: Yu
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Fu-Rong
authors.initials: FR
authors.lastname: Tian
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Mao
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.
authors.forename: Pian-Pian
authors.initials: PP
authors.lastname: Chen
authors.affiliation: College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: rarayier@gmail.com.
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Li
authors.affiliation: The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, China; College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: pharmtds@163.com.
authors.forename: Cui-Tao
authors.initials: CT
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D058065:Diabetic Cardiomyopathies / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D016220:Fibroblast Growth Factor 1 / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D006321:Heart / Q000503:physiopathology; D008297:Male; D051379:Mice; D045423:Microbubbles; D055806:Microvessels / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D041681:NIH 3T3 Cells; D053758:Nanoparticles / Q000008:administration & dosage* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D000069453:Ultrasonic Waves; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
chemical_list: D016220:Fibroblast Growth Factor 1; D051057:Proto-Oncogene Proteins c-akt
keywords: Diabetic cardiomyopathy; Nanoparticles; Preventive strategy; Ultrasound-targeted microbubble destruction technique; aFGF