Regulation of cGMP by glucose‐6‐phosphate dehydrogenase through PDE5 In coronary artery (849.2)

Abstract

Our laboratory has demonstrated that glucose‐6‐phosphate dehydrogenase (Glc‐6‐PD), the rate‐limiting enzyme in the pentose phosphate pathway, is a novel regulator of vascular smooth muscle contraction and phenotype. Inhibition of Glc‐6‐PD increases the contractile phenotype of coronary and pulmonary arteries by partly activating protein kinase G (PKG) pathway. PKG is activated by cyclic GMP (cGMP), which is increased in response to atrial natriuretic peptide (ANP) or nitric oxide and by inhibition of phosphodiesterase 5 (PDE5). Recently, using a combination of co‐immunoprecipitation and mass‐spec approach, we discovered that Glc‐6‐PD and PDE5 forms a complex in the coronary artery. Therefore, we hypothesized that inhibition of Glc‐6‐PD increases cGMP levels (which activates PKG) by decreasing the activity of PDE5 in coronary artery. To test our hypothesis, we incubated bovine left anterior descending artery (LAD) with Glc‐6‐PD inhibitors, 6‐aminonicotinamide (6‐AN, 1 µM) and dehydroepiandrosterone (DHEA, 100 µM); PDE5 inhibitor, sildenafil (Sil, 10 µM); Sil+6‐AN; and Sil+DHEA, in‐vitro for 12 hr and measured cGMP levels. Surprisingly and contrary to our expectations, we found that 6‐AN and DHEA decreased basal cGMP levels by 52 and 65%, respectively, as compared to control. While Sil increased cGMP by 324%, 6‐AN and DHEA reduced Sil‐induced increase in cGMP (Sil+6‐AN; 184% and Sil+DHEA; 133%). In conclusion, our novel findings demonstrate that: 1] inhibition of Glc‐6‐PD increases PKG activity via a cGMP‐independent pathway, 2] Glc‐6‐PD interacts with PDE5, and 3] Glc‐6‐PD‐derived redox signaling is an inhibitor of PDE5. These findings suggest that in diabetes or metabolic syndrome increased redox signaling may counter‐intuitively decrease the efficacy of PDE5 blockers.Grant Funding Source: NIHHL085352