Sildenafil and cardiomyocyte-specific cGMP signaling prevent cardiomyopathic changes associated with dystrophin deficiency.
We recently demonstrated early metabolic alterations in the dystrophin-deficient mdx heart that precede overt cardiomyopathy and may represent an early "subclinical" signature of a defective nitric oxide (NO)/cGMP pathway. In this study, we used genetic and pharmacological approaches to test the hypothesis that enhancing cGMP, downstream of NO formation, improves the contractile function, energy metabolism, and sarcolemmal integrity of the mdx heart. We first generated mdx mice overexpressing, in a cardiomyocyte-specific manner, guanylyl cyclase (GC) (mdx/GC(+/0)). When perfused ex vivo in the working mode, 12- and 20-week-old hearts maintained their contractile performance, as opposed to the severe deterioration observed in age-matched mdx hearts, which also displayed two to three times more lactate dehydrogenase release than mdx/GC(+/0). At the metabolic level, mdx/GC(+/0) displayed a pattern of substrate selection for energy production that was similar to that of their mdx counterparts, but levels of citric acid cycle intermediates were significantly higher (36 +/- 8%), suggesting improved mitochondrial function. Finally, the ability of dystrophin-deficient hearts to resist sarcolemmal damage induced in vivo by increasing the cardiac workload acutely with isoproterenol was enhanced by the presence of the transgene and even more so by inhibiting cGMP breakdown using the phosphodiesterase inhibitor sildenafil (44.4 +/- 1.0% reduction in cardiomyocyte damage). Overall, these findings demonstrate that enhancing cGMP signaling, specifically downstream and independent of NO formation, in the dystrophin-deficient heart improves contractile performance, myocardial metabolic status, and sarcolemmal integrity and thus constitutes a potential clinical avenue for the treatment of the dystrophin-related cardiomyopathies.
Khairallah
M
M
Montreal Heart Institute, Canada.
Khairallah
R J
RJ
Young
M E
ME
Allen
B G
BG
Gillis
M A
MA
Danialou
G
G
Deschepper
C F
CF
Petrof
B J
BJ
Des Rosiers
C
C
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D006152:Cyclic GMP / Q000378:metabolism*; D016189:Dystrophin / Q000172:deficiency*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*
D016189:Dystrophin; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009320:Atrial Natriuretic Factor; D000068677:Sildenafil Citrate; D006162:Guanylate Cyclase; D006152:Cyclic GMP