Cardiac unloading by LVAD support differentially influences components of the cGMP–PKG signaling pathway in ischemic and dilated cardiomyopathy

Abstract

Implantation of left ventricular assist devices (LVADs) as bridge to transplant in end-stage heart failure allows for analyzing reverse remodeling processes of the supported heart. Whether this therapy influences the cGMP-PKG signaling pathway, which is currently under thorough investigation for developing new heart failure therapeutics, is unknown. In fourteen end-stage heart failure patients (8 with dilated cardiomyopathy, DCM; 6 with ischemic cardiomyopathy, ICM) tissue specimens of left ventricles were collected at LVAD implantation and afterwards at receiver heart explantation, respectively. Then the expressions of key components of the cGMP-PKG signaling pathway were determined by polymerase chain reaction (ANP; BNP; natriuretic peptide receptor A, NPR-A; natriuretic peptide receptor C, NPR-C; neprilysin; NOS3; soluble guanylyl cyclase, sGC; PDE5; cGMP-dependent protein kinase G, PKG) and enzyme-linked immunosorbent assay (cGMP), respectively. Patients were predominantly male, 52 ± 10 years old, were receiving recommended heart failure therapy, and had their donor organ implanted after 351 ± 317 days of LVAD support. Except for more DCM patients with ICD therapy, no significant differences were detected between ICM and DCM, which also applies to the expression of cGMP-PKG pathway components at baseline. After LVAD support, ANP, NPR-C, and cGMP were significantly down-regulated and neprilysin, PDE5, and PKG I expressions were reduced with borderline significance in DCM, but not in ICM patients. Multiple significant correlations were found for expression differences (i.e., expression at LVAD implantation minus expression at heart transplantation) both in DCM and ICM, even though there was a closer connection between the NO and NP side of the cGMP-PKG pathway in DCM patients. Furthermore, duration of LVAD support negatively correlated with expression differences of PKG I, PDE5, and sGC in ICM, but not in DCM. Originating from the same activation level at LVAD implantation, cardiac unloading significantly alters key components of the cGMP-PKG pathway in DCM, but not in ICM patients. This etiology-specific regulation should be considered when analyzing therapeutic interventions with effects on this signaling pathway.

Exploring novel biomarkers in dilated cardiomyopathy‑induced heart failure by integrated analysis and in vitro experiments

“…Previous studies have indicated that aberrant JAK/STAT signaling may promote progression from hypertrophy to HF (43)(44)(45). In addition, the cGMP/PKG signaling pathway, adrenergic signaling in cardiomyocytes, and the p53 signaling pathway are also reportedly involved in the pathogenesis of HF (46)(47)(48)(49)(50)(51)(52). The enrichment findings of the present study are in line with the aforementioned conclusions, further strengthening the reliability of the present results.…”

Network Pharmacology Identifies the Mechanisms of Action of TaohongSiwu Decoction Against Essential Hypertension

“…The Calcium signaling pathway can increase calcium load and cause cardiovascular diseases such as arrhythmia [49]. The cGMP-PKG signaling pathway regulates vascular circulation and induces arterial relaxation [50].The cAMP signaling pathway is one of the signals activate G-protein in intracellular information transmission and activator by binding to specific receptors on the cell membrane, and then promote the transformation of adenosine triphosphate into cAMP [51]. The PI3K-Akt signaling pathway promotes the expression of PI3K, Akt proteins and activates thrombopoietin receptor-2, thus promoting neovascularization [52].…”

Myocardial Remodeling with Ventricular Assist Devices

“…Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from GTP (guanosine triphosphate) that acts as a second messenger for activation of intracellular protein kinases in response to the binding of membrane-impermeable hormones to the cell membrane [126]. The important components of cGMP signaling include cGMP-dependent protein kinase G (PKG), ANP, BNP, natriuretic peptide receptor A and C (NPR-A and NPR-C, respectively), neprilysin, NOS3, soluble guanylyl cyclase (sGC), and PDE5 [127]. The cGMP-PKG cascade can decrease the level of calcium and alter the expression of glycoprotein IIb/IIIa.…”