Guanylyl cyclase (GC)-A and GC-B activities in ventricles and cardiomyocytes from failed and non-failed human hearts: GC-A is inactive in the failed cardiomyocyte

• Published in: Journal of molecular and cellular cardiology 2012-03, Vol.52 (3), p.727-732
• Main Authors: Dickey, Deborah M, Dries, Daniel L, Margulies, Kenneth B, Potter, Lincoln R
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Atrial Natriuretic Factor - metabolism; Cardiovascular; Carperitide; cGMP; Enzyme Activation; Female; Heart failure; Heart Failure - enzymology; Heart Ventricles - enzymology; Humans; Male; Membrane Proteins - metabolism; Middle Aged; Myocytes, Cardiac - enzymology; Natriuretic peptide; Natriuretic peptide receptor A; Natriuretic Peptide, C-Type - metabolism; Nesiritide; Receptors, Atrial Natriuretic Factor - metabolism; Young Adult
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2011.11.007

Abstract Cardiomyocytes release atrial natriuretic peptide (ANP) and B-type natriuretic peptide to stimulate processes that compensate for the failing heart by activating guanylyl cyclase (GC)-A. C-type natriuretic peptide is also elevated in the failing heart and inhibits cardiac remodeling by activating the homologous receptor, GC-B. We previously reported that GC-A is the most active membrane GC in normal mouse ventricles while GC-B is the most active membrane GC in failing ventricles due to increased GC-B and decreased GC-A activities. Here, we examined ANP and CNP-specific GC activity in membranes obtained from non-failing and failing human left ventricles and in membranes from matched cardiomyocyte-enriched pellet preparations. Similar to our findings in the murine study, we found that CNP-dependent GC activity was about half of the ANP-dependent GC activity in the non-failing ventricular and was increased in the failing ventricle. ANP and CNP increased GC activity 9- and 5-fold in non-failing ventricles, respectively. In contrast to the mouse study, in failing human ventricles, ANP-dependent activity was unchanged compared to non-failing values whereas CNP-dependent activity increased 35% (p = 0.005). Compared with ventricular membranes, basal GC activity was reduced an order of magnitude in membranes derived from myocyte-enriched pellets from non-failing ventricles. ANP increased GC activity 2.4-fold but CNP only increased GC activity 1.3-fold. In contrast, neither ANP nor CNP increased GC activity in equivalent preparations from failing ventricles. We conclude that: 1) GC-B activity is increased in non-myocytes from failing human ventricles, possibly as a result of increased fibrosis, 2) human ventricular cardiomyocytes express low levels of GC-A and much lower levels or possibly no GC-B, and 3) GC-A in cardiomyocytes from failing human hearts is refractory to ANP stimulation.