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.
Bibliographical noteFunding Information:
This work was supported by the National Institutes of Health grants R21HL0934402 to LRP and R01HL089847 to KBM.
- Heart failure
- Natriuretic peptide
- Natriuretic peptide receptor A