transforming-growth-factor-beta and Peripheral-Vascular-Diseases

Recent data indicate that loss-of-function mutation in the gene encoding the facilitative glucose transporter GLUT10 (SLC2A10) causes arterial tortuosity syndrome via upregulation of the TGF-β pathway in the arterial wall, a mechanism possibly causing vascular changes in diabetes.. We genotyped 10 single nucleotide polymorphisms and one microsatellite spanning 34 kb across the SLC2A10 gene in a prospective cohort of 372 diabetic patients. Their association with the development of peripheral arterial disease (PAD) in type 2 diabetic patients was analyzed.. At baseline, several common SNPs of SLC2A10 gene were associated with PAD in type 2 diabetic patients. A common haplotype was associated with higher risk of PAD in type 2 diabetic patients (haplotype frequency: 6.3%, P = 0.03; odds ratio [OR]: 14.5; 95% confidence interval [CI]: 1.3- 160.7) at baseline. Over an average follow-up period of 5.7 years, carriers with the risk-conferring haplotype were more likely to develop PAD (P = 0.007; hazard ratio: 6.78; 95% CI: 1.66- 27.6) than were non-carriers. These associations remained significant after adjustment for other risk factors of PAD.. Our data demonstrate that genetic polymorphism of the SLC2A10 gene is an independent risk factor for PAD in type 2 diabetes.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Genotype; Glucose Transport Proteins, Facilitative; Haplotypes; Humans; Longitudinal Studies; Male; Middle Aged; Odds Ratio; Peripheral Vascular Diseases; Polymorphism, Single Nucleotide; Risk; Risk Factors; Transforming Growth Factor beta

To determine whether peripheral arterial disease is associated with high circulating levels of pro-inflammatory cytokines, independent of confounders.. Participants were 955 men and women aged 60 years and older representative of the population in 2 Italian communities (107 with peripheral arterial disease). Measurements included the ankle brachial index, comorbidities, total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels, and these inflammatory factors: albumin, alpha-2 macroglobulin, C-reactive protein, fibrinogen, interleukin (IL)-1beta, IL-1 receptor antagonist, IL-6, IL-6 receptor, IL-10, IL-18, tumor necrosis factor alpha, and transforming growth factor beta.. Adjusting for age, sex, body mass index, smoking, comorbidities, HDL-C, and total cholesterol, participants with peripheral arterial disease had higher levels of IL-1 receptor antagonist (147.97 vs 131.24 pg/mL, P = .002), IL-6 (1.65 vs 1.37 pg/mL, P = .026), fibrinogen (362.49 vs 345.50 mg/dL, P = .039), and C-reactive protein (3.18 vs 2.56 mg/dL, P = .043) compared with those without peripheral arterial disease. These associations were attenuated after additional adjustment for physical activity.. In a community population, peripheral arterial disease is associated with increased circulating levels of IL-6, IL-1 receptor antagonist, fibrinogen, and C-reactive protein compared to persons without peripheral arterial disease. Further study is needed to determine whether reducing levels of certain inflammatory factors lowers the incidence and progression of peripheral arterial disease.

Topics: Aged; Aged, 80 and over; alpha-Macroglobulins; Biomarkers; Body Mass Index; C-Reactive Protein; Cholesterol; Comorbidity; Cytokines; Female; Fibrinogen; Health Surveys; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukins; Italy; Male; Middle Aged; Motor Activity; Peripheral Vascular Diseases; Pulse; Sampling Studies; Serum Albumin; Sialoglycoproteins; Smoking; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Although hepatocyte growth factor (HGF), a novel angiogenic growth factor, plays an important role in angiogenesis, regulation of local HGF production under hypoxia has not yet been clarified in vascular smooth muscle cells (VSMC) and endothelial cells (EC). Thus, we have studied the role of HGF in hypoxia-induced endothelial injury and the regulation of local vascular HGF expression in response to hypoxia.. HGF attenuated hypoxia-induced endothelial cell death. Importantly, hypoxic treatment of EC resulted in a significant decrease in local HGF production according to the severity of hypoxia and increased VEGF. Similarly, hypoxia significantly decreased in mRNA and protein of HGF and increased VEGF production in VSMC. In organ culture system, local HGF production was also significantly decreased by hypoxia (P<0.01). Downregulation of HGF by hypoxia is due to a significant decrease in cAMP, as hypoxic treatment decreased cAMP, a stimulator of HGF. Although active TGF-beta, a suppressor of HGF, was increased at 72 hours after hypoxic treatment, treatment of anti-TGF-beta antibody did not attenuate decreased HGF production. Finally, rHGF was intra-arterially administered into unilateral hind limb ischemia rabbits, to evaluate in vivo angiogenic activity. Of importance, a single intra-arterial administration of rHGF reduced severe necrosis due to ischemia in rabbit muscle, accompanied by a significant increase in angiographic score (P<0.01).. Overall, these data demonstrated that hypoxic treatment of vascular cells significantly downregulated HGF production due to decreased cAMP, suggesting their potential roles in the pathophysiology of ischemic diseases. Moreover, administration of rHGF induced therapeutic angiogenesis, accompanied by improvement of necrotic changes in the ischemic hind limb model, as cytokine supplement therapy for peripheral arterial disease.

Topics: Animals; Cell Hypoxia; Down-Regulation; Endothelium, Vascular; Hepatocyte Growth Factor; Neovascularization, Pathologic; Peripheral Vascular Diseases; Rabbits; Transforming Growth Factor beta