Left Ventricular Radial Function Associated With Genetic Variation in the cGMP-Dependent Protein Kinase

Abstract

C yclic guanosine monophosphate (cGMP), an intracellular second messenger, exerts its action by cGMP-dependent protein kinases (PKG-1) and cGMP-regulated phoshodiesterases. In the cardiovascular system, cGMP signaling is an important regulator of endothelial cell, vascular smooth muscle, and cardiomyocyte function.1 Studies of isolated myocytes from wild-type and cardiac-specific PKG-1 knockout mice 2 demonstrated that cGMP-PKG-1 signaling mediates a negative inotropic effect. Furthermore, in cardiac myocytes, adenoviral expression of PKG-1 attenuated hypertrophy via inhibition of calcineurine-nuclear factor of activated T-cells signaling.3 A recent genome-wide association study 4 found that the common genetic variants (tag) in human PKG-1 gene (PRKG1) were significantly associated with changes in diastolic blood pressure in response to an acute salt load in 478 never-treated patients with hypertension.Taken together, the above observations raise the possibility that genetic variability in PRKG1 might affect left ventricular (LV) function and structure. In the Flemish Study on Environment, Genes, and Health Outcomes (FLEMENGHO), we therefore investigated whether LV function and structure were associated with tag PRKG1 polymorphisms. In this study, we assessed LV phenotypes by using classical M-mode and 2-dimensional echocardiography as well as tissue Doppler imaging, which is a sensitive technique to detect early stages of LV dysfunction. 5,6 Methods Study ParticipantsThe Ethics Committee of the University of Leuven approved the FLEMENGHO study. As described in detail in previous publications, 7,8 from August 1985 to December 2005, we recruited a random sample of families from a geographically defined area in northern Belgium. From May 2005 to April 2009, we reinvited 942 participants for a follow-up examination, including echocardiography, at our field center. We obtained informed written consent from 752 subjects (participation rate, 79.5%).From the current analysis, we excluded 67 subjects because of LV remodeling attributable to myocardial infarction or coronary revascularization (n=24), the presence of moderate or severe Abstract-cGMP-dependent protein kinase type I is a major mediator of cGMP signaling in the cardiovascular system.Recent studies on cardiac-specific PRKG1 knockout mice demonstrated that cGMP-dependent protein kinase type I mediates the negative inotropic effect of cGMP in the myocardium. We therefore investigated the association between left ventricular (LV) function and common polymorphisms in the PRKG1 gene in a general population. In 609 randomly selected participants (51.2% women; mean age, 48.8 years; 36.6% hypertensive) who were free from overt cardiac disease, we performed echocardiography and genotyped intronic tag single-nucleotide polymorphisms (SNPs) rs1904694, rs7897633, and rs7905063 in PRKG1. On the basis of color Doppler myocardial motion data, we calculated end-systolic longitudinal and radial deformation (strain) of the LV inferolateral wall. In multivariable-adjusted analy...

Pretreatment with Relaxin Does Not Restore NO-Mediated Modulation of Calcium Signal in Coronary Endothelial Cells Isolated from Spontaneously Hypertensive Rats

“…Chronically elevated blood pressure increases left ventricular (LV) pressure, enhances LV radial systolic performance and leads to LV hypertrophy. Recently, LV systolic radial deformation (strain) has been associated with common polymorphisms in PRKG1 [28]. In particular, LV radial systolic deformation is significantly higher in patients carrying PRKG1 homozygote polymorphism than in heterozygotes and noncarriers.…”

cGMP-Dependent Protein Kinase 1 Polymorphisms Underlie Renal Sodium Handling Impairment

“…Thus, the possible mechanisms connecting PRKG1 to salt-sensitive hypertension may be relevant to vascular 22 and cardiac complications. To address this point, Kuznetsova et al 23 investigated the role of PRKG1 polymorphisms in cardiac left ventricular dysfunctions in a cohort of a general population.…”

Genetics of NO Deficiency

“…49,50 In 609 participants from the Flemish Study on Environment, Genes, and Health Outcomes, the same 3 SNPs were associated with LV function, with significantly higher LV systolic radial strain for homozygotes for G, A, and T (rs1904694: GG vs GA or AA, p = 0.0016; rs7897633: AA vs AC or CC, p = 0.0003; rs7905063: TT vs TC or CC, p = 0.0033). 51 In addition, the GAT haplotype was associated with LV radial systolic strain (p = 0.0005). 51 Notably, PKG1-mediated phosphorylation can modulate other proteins in the NO-cGMP pathway, including sGC (upstream of PKG1) and phosphodiesterase (PDE)5 (downstream of PKG1).…”

“…51 In addition, the GAT haplotype was associated with LV radial systolic strain (p = 0.0005). 51 Notably, PKG1-mediated phosphorylation can modulate other proteins in the NO-cGMP pathway, including sGC (upstream of PKG1) and phosphodiesterase (PDE)5 (downstream of PKG1). 52,53 Phosphodiesterase 5A…”