Sildenafil Improves Exercise Capacity and Quality of Life in Patients with Systolic Heart Failure and Secondary Pulmonary Hypertension

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• 作者：Gregory D. Lewis ; Ravi Shah ; Khurram Shahzad ; Janice Camuso ; Paul P. Pappagianopoulos ; Judy Hung ; Ahmed Tawakol ; Robert E. Gerszten ; David M. Systrom ; Kenneth D. Bloch ; Marc J. Semigran
• 关键词：Human heart ; NAD(P)H oxidase ; glucose-6-phosphate dehydrogenase ; protein kinase C ; Src kinase ; free radicals
• 刊名：Journal of Cardiac Failure
• 出版年：2007
• 出版时间：August 2007
• 年：2007
• 卷：13
• 期：6, Supplement 2
• 页码：S135-S136
• 全文大小：285 K

文摘

We previously found that higher NADPH levels produced by glucose-6-phosphate dehydrogenase (G6PD) can enhance myocardial superoxide generation by NAD(P)H oxidase in a dog model of dilated cardiomyopathy. Therefore, we tested whether G6PD activity is elevated and enhances NADPH level and increases NAD(P)H oxidase-derived superoxide production in the myocardium from patients with heart failure from ischemic cardiomyopathy.

Methods and Results

Surgical discards of left ventricle were collected from 8 congestive heart failure patients undergoing surgical ventricular restoration procedures, whereas control left ventricle tissue was obtained from 5 normal donor hearts deemed not suitable for transplantation. Biochemical assays were performed in tissue homogenates. We found that superoxide and hydrogen peroxide were elevated, respectively, by 9- and 3-fold in failing versus normal hearts (P < .05). The NAD(P)H oxidase inhibitors gp91^ds-tat, apocynin, and diphenyleneiodonium, significantly inhibited superoxide generation by approximately 75 % , 89 % , and 91 % , respectively. Superoxide production by NAD(P)H oxidase increased 10- and 3-fold by adding NADPH (100 μmol/L) and NADH (100 μmol/L), respectively, in a DPI- and gp91^ds-tat–inhibitable manner. Interestingly, chelerythrine, a PKC inhibitor, and PP2, a Src kinase family inhibitor, reduced G6PD activity (0.29 ± 0.04 nM·min·mg protein) by 50 % and 51 % and these inhibitors also decreased myocardial superoxide by 99 % and 79 % , respectively. Furthermore, 6-aminonicotinamide, a G6PD inhibitor, decreased myocardial superoxide production by 71 % .

Conclusions

These data suggest that high NAD(P)H oxidase, fueled by G6PD-derived NADPH, generates most of the superoxide in failing hearts of patients with ischemic cardiomyopathy. In addition, PKC-Src kinase signaling pathways seem to coordinate the activation of both G6PD and NAD(P)H oxidase in human cardiac muscle.