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Coronary endothelial dysfunction in the insulin-resistant state is linked to abnormal pteridine metabolism and vascular oxidative stress

Kazuya Shinozaki, MD, PhD^*, Atsushi Hirayama, MD, PhD, Yoshihiko Nishio, MD, PhD, Yuichi Yoshida, PhD, Tomohito Ohtani, MD, Tomio Okamura, MD, PhD^*, Masahiro Masada, PhD, Ryuichi Kikkawa, MD, PhD, Kazuhisa Kodama, MD, PhD and Atsunori Kashiwagi, MD, PhD^*,

^* Department of Pharmacology, Shiga University of Medical Science, Seta, Otsu, Shiga, Japan
Third Department of Medicine, Shiga University of Medical Science, Seta, Otsu, Shiga, Japan
Cardiovascular Division, Osaka Police Hospital, Kitayama-cho, Tennoji-ku Osaka, Japan
Laboratory of Biochemistry, Faculty of Horticulture, Chiba University, Matsudo, Chiba, Japan

View larger version (18K): [in a new window]   Figure 1 Percent changes in left anterior descending artery (LAD) diameters from baseline values in response to intracoronary infusion of graded dose (50 µg, 100 µg) of acetylcholine (ACh) and to 0.3 mg of nitroglycerin (NTG) categorized by tertiles of insulin sensitivity in patients with normal coronary angiogram (n = 36). IS = insulin sensitive (open bars); BL = borderline (solid bars); IR = insulin resistant (hatched bars). *p < 0.05 vs. IS. p < 0.05 vs. BL.

View larger version (35K): [in a new window]   Figure 2 Correlation between percent changes in left anterior descending artery (LAD) diameters from baseline values in response to intracoronary infusion of 100 µg acetylcholine (ACh) and 2-h insulin area, plasma lipid hydroperoxide (TBARS) level of coronary sinus-arterial (CS-Ao) difference, BH4/7,8-BH2 + biopterin, and dihydropteridine reductase (DHPR) activity in study subjects (n = 36). BH4 = tetrahydrobiopterin; BH2 = dihydrobiopterin.

View larger version (24K): [in a new window]   Figure 3 Hypothetical scheme illustrating the possible mechanism of impaired endothelial function in the insulin-resistant state. Increased quinonoid dihydrobiopterin (qBH2) synthesis in the insulin-resistant state is closely associated with a decrement in the activity of dihydropteridine reductase (DHPR), the recycling enzyme that converts BH2 to tetrahydrobiopterin (BH4). As a result, both BH4/BH2 ratio and BH4 to total biopterin (BH2 + BH4) were significantly decreased in the insulin-resistant subjects. These results indicate that decreased nitric oxide (NO)-dependent vasodilation in the insulin-resistant state may be related to abnormal pteridine metabolism and vascular oxidative stress. GTP = guanosine triphosphate; eNOS = endothelial nitric oxide synthase; O2– = superoxide anion; PTPS = 6-pyruvoyltetrahydropterine synthase; SR = sepiapterin reductase.