TY - JOUR
T1 - Arginase II deletion increases corpora cavernosa relaxation in diabetic mice
AU - Toque, Haroldo A.
AU - Tostes, Rita C.
AU - Yao, Lin
AU - Xu, Zhimin
AU - Webb, R. Clinton
AU - Caldwell, Ruth B.
AU - Caldwell, R. William
N1 - Funding Information:
This study was supported by NIH grants HL‐70215 and EY‐11766 to RWC and RBC.
PY - 2011/3
Y1 - 2011/3
N2 - Introduction. Diabetes-induced erectile dysfunction involves elevated arginase (Arg) activity and expression. Because nitric oxide (NO) synthase and Arg share and compete for their substrate L-arginine, NO production is likely linked to regulation of Arg. Arg is highly expressed and implicated in erectile dysfunction. Aim. It was hypothesized that Arg-II isoform deletion enhances relaxation function of corpora cavernosal (CC) smooth muscle in a streptozotocin (STZ) diabetic model. Methods. Eight weeks after STZ-induced diabetes, vascular functional studies, Arg activity assay, and protein expression levels of Arg and constitutive NOS (using Western blots) were assessed in CC tissues from nondiabetic wild type (WT), diabetic (D) WT (WT+D), Arg-II knockout (KO), and Arg-II KO+D mice (N=8-10 per group). Main Outcome Measures. Inhibition or lack of arginase results in facilitation of CC relaxation in diabetic CC. Results. Strips of CC from Arg-II KO mice exhibited an enhanced maximum endothelium-dependent relaxation (from 70+3% to 84+4%) and increased nitrergic relaxation (by 55%, 71%, 42%, 42%, and 24% for 1, 2, 4, 8 and 16Hz, respectively) compared with WT mice. WT+D mice showed a significant reduction of endothelium-dependent maximum relaxation (44+8%), but this impairment of relaxation was significantly prevented in Arg-II KO+D mice (69+4%). Sympathetic-mediated and alpha-adrenergic agent-induced contractile responses also were increased in CC strips from D compared with non-D controls. Contractile responses were significantly lower in Arg-II KO control and D versus the WT groups. WT+D mice increased Arg activity (1.5-fold) and Arg-II protein expression and decreased total and phospho-eNOS at Ser-1177, and nNOS levels. These alterations were not seen in Arg-II KO mice. Additionally, the Arg inhibitor BEC (50μM) enhanced nitrergic and endothelium-dependent relaxation in CC of WT+D mice. Conclusion. These studies show for the first time that Arg-II deletion improves CC relaxation in type 1 diabetes.
AB - Introduction. Diabetes-induced erectile dysfunction involves elevated arginase (Arg) activity and expression. Because nitric oxide (NO) synthase and Arg share and compete for their substrate L-arginine, NO production is likely linked to regulation of Arg. Arg is highly expressed and implicated in erectile dysfunction. Aim. It was hypothesized that Arg-II isoform deletion enhances relaxation function of corpora cavernosal (CC) smooth muscle in a streptozotocin (STZ) diabetic model. Methods. Eight weeks after STZ-induced diabetes, vascular functional studies, Arg activity assay, and protein expression levels of Arg and constitutive NOS (using Western blots) were assessed in CC tissues from nondiabetic wild type (WT), diabetic (D) WT (WT+D), Arg-II knockout (KO), and Arg-II KO+D mice (N=8-10 per group). Main Outcome Measures. Inhibition or lack of arginase results in facilitation of CC relaxation in diabetic CC. Results. Strips of CC from Arg-II KO mice exhibited an enhanced maximum endothelium-dependent relaxation (from 70+3% to 84+4%) and increased nitrergic relaxation (by 55%, 71%, 42%, 42%, and 24% for 1, 2, 4, 8 and 16Hz, respectively) compared with WT mice. WT+D mice showed a significant reduction of endothelium-dependent maximum relaxation (44+8%), but this impairment of relaxation was significantly prevented in Arg-II KO+D mice (69+4%). Sympathetic-mediated and alpha-adrenergic agent-induced contractile responses also were increased in CC strips from D compared with non-D controls. Contractile responses were significantly lower in Arg-II KO control and D versus the WT groups. WT+D mice increased Arg activity (1.5-fold) and Arg-II protein expression and decreased total and phospho-eNOS at Ser-1177, and nNOS levels. These alterations were not seen in Arg-II KO mice. Additionally, the Arg inhibitor BEC (50μM) enhanced nitrergic and endothelium-dependent relaxation in CC of WT+D mice. Conclusion. These studies show for the first time that Arg-II deletion improves CC relaxation in type 1 diabetes.
KW - Arginase
KW - Diabetes
KW - Erectile Dysfunction
KW - Nitric Oxide
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U2 - 10.1111/j.1743-6109.2010.02098.x
DO - 10.1111/j.1743-6109.2010.02098.x
M3 - Article
C2 - 21054801
AN - SCOPUS:79951976114
SN - 1743-6095
VL - 8
SP - 722
EP - 733
JO - Journal of Sexual Medicine
JF - Journal of Sexual Medicine
IS - 3
ER -