Abstract 18560: Myocardial-specific Overexpression of GTP Cyclohydrolase 1 Prevents Diabetic Cardiomyopathy Independent of Nitric Oxide
Background: Diabetic cardiomyopathy is characterised by significant left ventricular (LV) diastolic dysfunction. Increased oxidative stress and reduced nitric oxide (NO) availability secondary to oxidation of the NOS cofactor tetrahydrobiopterin (BH4) account for endothelial dysfunction in diabetes (DM). Here we tested whether myocardial-specific overexpression of the GTP-cyclohydrolase 1 (GCH1, the rate limiting enzyme in BH4 synthesis) prevents LV dysfunction in a murine model of DM by redressing the myocardial NO-redox balance
Methods & Results: DM was induced by streptozotocin (43 mg/kg/day for 5 days) in mice with αMHC-driven overexpression of human GCH1 (Tg) and their WT littermates. In the aorta, DM (12 weeks) impaired endothelium-dependent vasodilation, increased superoxide production (by 62%, P<0.05; lucigenin chemiluminescence, n=11-16) and reduced BH4 availability (by 35%, P<0.05; HPLC, n=6-10) in both genotypes. By contrast, LV homogenates from DM WT and Tg mice showed no evidence of increased superoxide production or BH4 depletion (n= 10-12, P=0.62 and P=0.82, respectively); similarly, total LV NOS activity was unchanged (P=0.68, n=5). Nevertheless, the LV diastolic dysfunction (Vevo2100, Visual Sonics) observed in DM WT mice was prevented in DM Tg mice (E’/A’ - DM vs control: 1.0 ± 0.3 vs 1.4 ± 0.1 in WT and 1.6 ± 0.1 vs 1.5 ± 0.1 in Tg; n=12-16 per group; P<0.01 for the interaction between genotype and DM). In line with these results, LV myocyte relaxation and decay of the [Ca2+]i transient was prolonged in DM WT but not in DM Tg (t50 in ms, DM vs control: 43 ± 2 vs. 37 ± 2 in WT and 26 ± 1 vs. 26 ± 1 in mGCH1 Tg; n=57-65 cells per group; P<0.05 for the interaction between genotype and DM). LV collagen content was significantly increased in DM but did not differ between genotypes.
Conclusions: Impaired LV diastolic function in DM can be prevented by myocardial GCH1 overexpression in the absence of NOS dysfunction, increased oxidative stress or changes in LV fibrosis, suggesting that GCH1/BH4 protect the DM myocardium by mechanisms other than redressing the local nitroso-redox balance.
Author Disclosures: R. Carnicer Hijazo: None. D. Duglan: None. J.N. Simon: None. S. Chuaiphichai: None. A. Hale: None. K.M. Channon: None. B. Casadei: None.
- © 2014 by American Heart Association, Inc.