Sildenafil and cardiomyocyte-specific cGMP signaling prevent cardiomyopathic changes associated with dystrophin deficiency

<jats:p> We recently demonstrated early metabolic alterations in the dystrophin-deficient <jats:italic>mdx</jats:italic> 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 <jats:italic>mdx</jats:italic> heart. We first generated <jats:italic>mdx</jats:italic> mice overexpressing, in a cardiomyocyte-specific manner, guanylyl cyclase (GC) ( <jats:italic>mdx</jats:italic> /GC <jats:sup>+/0</jats:sup> ). When perfused <jats:italic>ex vivo</jats:italic> in the working mode, 12- and 20-week-old hearts maintained their contractile performance, as opposed to the severe deterioration observed in age-matched <jats:italic>mdx</jats:italic> hearts, which also displayed two to three times more lactate dehydrogenase release than <jats:italic>mdx</jats:italic> /GC <jats:sup>+/0</jats:sup> . At the metabolic level, <jats:italic>mdx</jats:italic> /GC <jats:sup>+/0</jats:sup> displayed a pattern of substrate selection for energy production that was similar to that of their <jats:italic>mdx</jats:italic> 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 <jats:italic>in vivo</jats:italic> 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. </jats:p>