Cyclic GMP-Dependent Signaling in Cardiac Myocytes

Nitric Oxide-cGMP-PKG Pathway Acts on Orai1 to Inhibit the Hypertrophy of Human Embryonic Stem Cell-Derived Cardiomyocytes

“…Previously, research in rodent models has demonstrated that SOCE, STIM1, and Orai1 play crucial roles in the development of cardiomyocyte hypertrophy [8][9][10], whereas NO, cGMP, and PKG exert antihypertrophic effect [6,11,34]. However, one of the challenges in exploring mechanistic insight of Orai1 and/or NO-cGMP-PKG effect is lack of human cardiomyocytes for research.…”

“…Along this line, sildenafil, a cGMP-phosphodiesterase inhibitor that raises cytosolic cGMP level and thus stimulates PKG, has been shown to ameliorate cardiac hypertrophy and remodeling [6]. Furthermore, administration of NO donors to patients with cardiac hypertrophy improves cardiac function [12].…”

B-Type Natriuretic Peptide in Heart Failure With Preserved Ejection Fraction ― Relevance to Age-Related Left Ventricular Modeling in Japanese ―

“…6-9 However, sildenafil, an inhibitor of phosphodiesterase 5 (PDE5), which predominantly degrades NO-derived cGMP, failed to ameliorate HFpEF, 36 probably because PDE5 as well as NO-derived cGMP is reduced. [28][29][30][31][32][33] It is interesting to note in this connection that an inhibitor of neprilysin, which degrades natriuretic peptides, including BNP, had beneficial effects on HFpEF 37 and that PDE 9A rather than PDE5 degrades natriuretic peptides and its inhibition protects against HFpEF independent of NO-derived cGMP activity. 38 Suppression of chronic systemic inflammation and increased systolic blood pressure together with pulse pressure are therefore expected to be effective for HFpEF particularly in those with predominant or isolated systolic hypertension.…”

Impact of Comorbidities on Myocardial Remodeling and Dysfunction In Heart Failure with Preserved Ejection Fraction

“…Hypophosphorylation of titin resulted from lower myocardial PKG activity and reduced myocardial cyclic guanosine monophosphate (cGMP) concentration in HFpEF compared to HFrEF and AS [37] (Figure 2A). Myocardial PKG plays a pivotal role in normal cardiovascular physiology and PKG phosphorylates a vast number of target proteins, exerting a wide range of downstream effects, such as inhibition of the L-type calcium channel, enhancement of intracellular diastolic calcium reuptake through phosphorylation of phospholamban (PLB), suppression of hypertrophic signaling through inhibition of G-protein coupled receptors and the transient receptor potential canonical channel, inhibition of ischemia-reperfusion injury through phosphorylation of the ATP-sensitive potassium channel and stimulation of LV relaxation and distensibility by phosphorylation of troponin I (TnI) and titin(Figure1) [38]. Myocardial cGMP-PKG signaling is coupled upstream to stimulation by two distinct pathways including the natriuretic peptide (NP)-particulate guanylate cyclase (pGC) pathway and the nitric oxide (NO)-soluble GC (sGC) pathway [38] (Figure 1).…”

“…Myocardial PKG plays a pivotal role in normal cardiovascular physiology and PKG phosphorylates a vast number of target proteins, exerting a wide range of downstream effects, such as inhibition of the L-type calcium channel, enhancement of intracellular diastolic calcium reuptake through phosphorylation of phospholamban (PLB), suppression of hypertrophic signaling through inhibition of G-protein coupled receptors and the transient receptor potential canonical channel, inhibition of ischemia-reperfusion injury through phosphorylation of the ATP-sensitive potassium channel and stimulation of LV relaxation and distensibility by phosphorylation of troponin I (TnI) and titin(Figure1) [38]. Myocardial cGMP-PKG signaling is coupled upstream to stimulation by two distinct pathways including the natriuretic peptide (NP)-particulate guanylate cyclase (pGC) pathway and the nitric oxide (NO)-soluble GC (sGC) pathway [38] (Figure 1). Although myocardial brain-type natriuretic peptide (BNP) expression is lower in HFpEF than in HFrEF, the significantly reduced myocardial cGMP-PKG activity in HFpEF, compared to HFrEF and AS could not be explained by lower myocardial BNP expression alone [37].…”