Human Apolipoprotein A-I Gene Transfer Reduces the Development of Experimental Diabetic Cardiomyopathy

Abteilung für Kardiologie und Pneumologie, Charité-Universitätsklinikum Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
Circulation (Impact Factor: 14.43). 04/2008; 117(12):1563-73. DOI: 10.1161/CIRCULATIONAHA.107.710830
Source: PubMed


The hallmarks of diabetic cardiomyopathy are cardiac oxidative stress, intramyocardial inflammation, cardiac fibrosis, and cardiac apoptosis. Given the antioxidative, antiinflammatory, and antiapoptotic potential of high-density lipoprotein (HDL), we evaluated the hypothesis that increased HDL via gene transfer (GT) with human apolipoprotein (apo) A-I, the principal apolipoprotein of HDL, may reduce the development of diabetic cardiomyopathy.
Intravenous GT with 3x10(12) particles/kg of the E1E3E4-deleted vector Ad.hapoA-I, expressing human apoA-I, or Ad.Null, containing no expression cassette, was performed 5 days after streptozotocin (STZ) injection. Six weeks after apoA-I GT, HDL cholesterol levels were increased by 1.6-fold (P<0.001) compared with diabetic controls injected with the Ad.Null vector (STZ-Ad.Null). ApoA-I GT and HDL improved LV contractility in vivo and cardiomyocyte contractility ex vivo, respectively. Moreover, apoA-I GT was associated with decreased cardiac oxidative stress and reduced intramyocardial inflammation. In addition, compared with STZ-Ad.Null rats, cardiac fibrosis and glycogen accumulation were reduced by 1.7-fold and 3.1-fold, respectively (P<0.05). Caspase 3/7 activity was decreased 1.2-fold (P<0.05), and the ratio of Bcl-2 to Bax was upregulated 1.9-fold (P<0.005), translating to 2.1-fold (P<0.05) reduced total number of cardiomyocytes with apoptotic characteristics and 3.0-fold (P<0.005) reduced damaged endothelial cells compared with STZ-Ad.Null rats. HDL supplementation ex vivo reduced hyperglycemia-induced cardiomyocyte apoptosis by 3.4-fold (P<0.005). The apoA-I GT-mediated protection was associated with a 1.6-, 1.6-, and 2.4-fold induction of diabetes-downregulated phospho to Akt, endothelial nitric oxide synthase, and glycogen synthase kinase ratio, respectively (P<0.005).
ApoA-I GT reduced the development of streptozotocin-induced diabetic cardiomyopathy.

16 Reads
  • Source
    • "Consistent with previous study, diabetic rats in our study displayed overt intramyocardial inflammation 7 weeks after STZ injection [15], as evidenced by enhanced activity and expression of NF-κB p65, thus leading to increased levels of cardiac pro-inflammatory cytokines (TNF-α, IL-1β), enhanced expressions of cell adhesion molecules (ICAM-1, VCAM-1), and activated invading immunocompetent cells (macrophages, T lymphocytes). In addition, cardiac collagen content (total collagen, collagen I and collagen III) was also significantly increased in these untreated rats. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Aims Given the importance of inflammation in the onset and progression of diabetic cardiomyopathy, we investigated the potential protective effects of triptolide, an anti-inflammatory agent, in streptozotocin-induced diabetic rat model and in H9c2 rat cardiac cells exposed to high glucose. Methods and results Diabetic rats were treated with triptolide (100, 200, or 400 μg/kg/day respectively) for 6 weeks. At the end of this study, after cardiac function measurements were performed, rats were sacrificed and their hearts were harvested for further histologic and molecular biologic analysis. Enhanced activity and expression of nuclear factor-kappaB (NF-κB) p65 in diabetic hearts were associated with increased inflammatory response, as demonstrated by increased pro-inflammatory cytokines, cell adhesion molecules and invading inflammatory cells, as well as increased fibrosis, in line with impaired left ventricular function. Triptolide attenuated these morpho-functional alterations. Furthermore, triptolide (20 ng/ml) also attenuated high glucose-induced inflammation in H9c2 rat cardiac cells. Conclusion Our data demonstrate that anti-inflammatory effects of triptolide involving the NF-κB signaling pathway can improve left ventricular function under diabetic conditions, suggesting triptolide treatment might be beneficial in diabetic cardiomyopathy.
    Cardiovascular Diabetology 03/2013; 12(1):50. DOI:10.1186/1475-2840-12-50 · 4.02 Impact Factor
  • Source
    • "HDL has multiple endothelial actions which afford cardiovascular protection [4], [6], among which, EC proliferation and migration may play a crucial role in vascular self-repair. Decreased plasma HDL cholesterol concentration in diabetic patients is frequently associated with endothelial dysfunction, and clinical studies demonstrate that increased levels of HDL can reduce the risk of atherosclerosis progression in diabetic patients [7], [8]. Furthermore, D-HDL has impaired ability to activate eNOS, and EPC related early repair [11], [25]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Diabetic HDL had diminished capacity to stimulate endothelial cell (EC) proliferation, migration, and adhesion to extracellular matrix. The mechanism of such dysfunction is poorly understood and we therefore sought to determine the mechanistic features of diabetic HDL dysfunction. Methodology/Principal Findings We found that the dysfunction of diabetic HDL on human umbilical vein endothelial cells (HUVECs) was associated with the down regulation of the HDL receptor protein, SR-BI. Akt-phosphorylation in HUVECs was induced in a biphasic manner by normal HDL. While diabetic HDL induced Akt phosphorylation normally after 20 minutes, the phosphorylation observed 24 hours after diabetic HDL treatment was reduced. To determine the role of SR-BI down regulation on diminished EC responses of diabetic HDL, Mouse aortic endothelial cells (MAECs) were isolated from wild type and SR-BI (−/−) mice, and treated with normal and diabetic HDL. The proliferative and migratory effects of normal HDL on wild type MAECs were greatly diminished in SR-BI (−/−) cells. In contrast, response to diabetic HDL was impaired in both types suggesting diminished effectiveness of diabetic HDL on EC proliferation and migration might be due to the down regulation of SR-BI. Additionally, SR-BI down regulation diminishes diabetic HDL’s capacity to activate Akt chronically. Conclusions/Significance Diabetic HDL was dysfunctional in promoting EC proliferation, migration, and adhesion to matrix which was associated with the down-regulation of SR-BI. Additionally, SR-BI down regulation diminishes diabetic HDL’s capacity to activate Akt chronically.
    PLoS ONE 11/2012; 7(11):e48530. DOI:10.1371/journal.pone.0048530 · 3.23 Impact Factor
  • Source
    • "Diabetes and its several complications are a major public health problem (28). Accumulating evidence from epidemiological data and animal and clinical studies shows that the risk of heart failure is considerably increased by diabetes, and diabetes has been recognized as one of the major risk factors for the development of heart failure (28,29). Nonetheless, the pathophysiology of diabetic cardiomyopathy remains uncertain and novel therapeutic strategies for its prevention and rescue are needed. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes is a cause of cardiac dysfunction, reduced myocardial perfusion, and ultimately heart failure. Nerve growth factor (NGF) exerts protective effects on the cardiovascular system. This study investigated whether NGF gene transfer can prevent diabetic cardiomyopathy in mice. We worked with mice with streptozotocin-induced type 1 diabetes and with nondiabetic control mice. After having established that diabetes reduces cardiac NGF mRNA expression, we tested NGF gene therapies with adeno-associated viral vectors (AAVs) for the capacity to protect the diabetic mouse heart. To this aim, after 2 weeks of diabetes, cardiac expression of human NGF or β-Gal (control) genes was induced by either intramyocardial injection of AAV serotype 2 (AAV2) or systemic delivery of AAV serotype 9 (AAV9). Nondiabetic mice were given AAV2-β-Gal or AAV9-β-Gal. We found that the diabetic mice receiving NGF gene transfer via either AAV2 or AAV9 were spared the progressive deterioration of cardiac function and left ventricular chamber dilatation observed in β-Gal-injected diabetic mice. Moreover, they were additionally protected from myocardial microvascular rarefaction, hypoperfusion, increased deposition of interstitial fibrosis, and increased apoptosis of endothelial cells and cardiomyocytes, which afflicted the β-Gal-injected diabetic control mice. Our data suggest therapeutic potential of NGF for the prevention of cardiomyopathy in diabetic subjects.
    Diabetes 01/2012; 61(1):229-40. DOI:10.2337/db11-0763 · 8.10 Impact Factor
Show more


16 Reads
Available from