Regulation and role of myocyte cyclic GMP-dependent protein kinase-1

Abstract

We were intrigued with the study by Lukowski et al. (1), which investigated mice lacking cGMP-activated kinase (cGK1α and cGK1β) in all cells except those with smooth muscle (sm22) promoter activity (cGK1β-rescue) and concluded that cardiomyocyte cGK1 does not modify hypertrophic responses to β-adrenergic or pressure stress. As this study appears to counter prior work suggesting cGK1 suppresses myocyte hypertrophy, we felt it was important to point out some alternative interpretations to the readers. For example, their conclusions presume that cGK1 activity rose sufficiently in wild-type controls with their stress models, but this was not confirmed. Basal myocyte cGK1 activity is low, yet it may confer potent brake-like effects if sufficiently activated. The authors did not test if antihypertrophic effects of nitric oxide, natriuretic peptides, or other methods to stimulate cGMP levels are myocyte cGK1-independent, which is unlikely. Antihypertrophic action also requires that relevant cGK1 targets (e.g., calcineurin and Gαq cascades) be stimulated, which depends on the mode and extent of stress. Sildenafil [phosphodiesterase type 5 (PDE5) inhibitor] augments cGK1 activity similarly in moderate and severe pressure overload but suppresses hypertrophy more in severe overload where cGK1-targeted signaling is activated (2). In Lukowski et al. (1), isoproterenol and pressure overload yielded modest 20–40% increases in left ventricular mass (figures showed higher values because of an unexplained decline in body weight), suggesting that cGK1-targeted cascades may not have been activated. Last, cardiac characteristics of the genetic model were not fully described, although it displays time-dependent increased mortality by 1 year. This is especially relevant, because the rescue model is created in mice harboring a complete cGK1 deletion that cannot be bred because of early mortality and the mice are rescued in the vasculature only.