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Although NO-induced cGMP has a long-known function in the vascular system, its function in the heart is less well established. In cardiac slices of healthy mice, NO-induced cGMP enters cardiac myocytes through gap junctions -as shown using a FRET-based cGMP indicator specifically expressed in cardiac myocytes- and amplifies β-receptor-induced cAMP by inhibiting PDE3.To identify the source of NO-induced cGMP, mice devoid of NO-sensitive guanylyl cyclase 1 (NO-GC1) specifically in Tcf21-expressing fibroblasts were generated. In acute slices of these mice, NO-GC stimulators did no longer enhance isoprenaline-stimulated cAMP in cardiac myocytes and did not enhance isoprenaline-induced phospholamban phosphorylation.To investigate whether the function of NO-induced cGMP is altered under pathophysiological condi-tions, Angiotensin II-treated mice with cardiac hypertrophy were analysed. In these mice, expression of PDE2 (cGMP-stimulated phosphodiesterase) was increased and PDE2 gained a stronger impact on NO-induced cGMP as analysed by the FRET-based cGMP indicator cGi-500. Accordingly, NO-induced cGMP was shown to decrease cAMP and phospholamban phosphorylation. Interestingly, basal cAMP levels as well as phospholamban phosphorylation were increased compared to untreated mice.In sum, Tcf21-expressing cardiac fibroblasts were identified as source of NO-induced cGMP in cardiac myocytes. Cardiac hypertrophy reversed the effect of NO-induced cGMP on cAMP in myocytes. Instead of increasing cAMP and phospholamban phosphorylation via PDE3 as observed under control conditi¬ons, NO-induced cGMP decreased cAMP and phospholamban phosphorylation via PDE2 in Angio¬tensin II-induced hypertrophy.
Giesen et al. (Sat,) studied this question.