Modulation of In Vivo Cardiac Function by Myocyte-Specific Nitric Oxide Synthase-3

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Abstract
Nitric oxide (NO) functions principally as a diffusible paracrine effector. The exception is in cardiomyocytes where both NO synthases (NOS) and target proteins coexist, allowing NO to work in an autocrine/intracrine fashion. However, the most abundant myocyte isoform (NOS3) is far more expressed in vascular endothelium; thus, the in vivo contribution of myocyte-NOS3 remains less clear. The present study tested this role by transfecting whole hearts of NOS3-null (NOS3 −/− ) mice with adenovirus-expressing NOS3 coupled to a α-MHC promoter (AdV NOS3 ), comparing results to hearts transfected with marker-gene β-galactosidase (AdVβ gal ). Total myocardial NOS3 protein and activity were restored to near wild-type (WT) levels in NOS3 −/− +AdV NOS3 hearts, and NOS3 relocalized normally with caveolin-3. Ejection function by pressure-volume analysis was enhanced in NOS3 −/− +AdVβ gal over WT or NOS3 −/− +AdV NOS3 . More prominently, isoproterenol (ISO)-stimulated systolic and diastolic function in WT was amplified in NOS3 −/− +AdVβ gal , whereas NOS3 −/− +AdV NOS3 returned the response to control. ISO-activated systolic function was inhibited 85% by concomitant muscarinic stimulation (carbachol) in NOS3 −/− +AdV NOS3 but not NOS3 −/− +AdVβ gal hearts. Lastly, NOS3 −/− +AdVβ gal mice displayed enhanced inotropy and lusitropy over WT at slower heart rates but a blunted rate augmentation versus controls. A more positive rate response was restored in NOS3 −/− +AdV NOS3 ( P <0.001). Thus, myocyte autocrine/intracrine NOS3 regulation in vivo can underlie key roles in β-adrenergic, muscarinic, and frequency-dependent cardiac regulation.