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- Title
Increased effects of C-type natriuretic peptide on contractility and calcium regulation in murine hearts overexpressing cyclic GMP-dependent protein kinase I.
- Authors
Wollert, Kai C.; Yurukova, Sevdalina; Kilic, Ana; Begrow, Frank; Fiedler, Beate; Gambaryan, Stepan; Walter, Ulrich; Lohmann, Suzanne M.; Kuhn, Michaela
- Abstract
1 C-type natriuretie peptide (CNP) and its raceptor guanylyl cyclase (GC-B) are expressed in the heart and modulate cardiac contractility in a cGMP-dependent manner. Since the distal cellular signalling pathways remain unclear, we evaluated the peptide effects on cardiac function and calcium regulation in wild-type (WT) and transgemc mice with cardiac overexpression cGMP-dependent protein kinase I (PKG 1[SupTG]). 2 In isolated, pefused working WT hearts, CNP (10nM) provoked an immediate increase in the maximal rates of contraction and relaxation, a small increase in the left ventricular systolic pressure and a decrease in the time of relaxation. These changes in cardiac Function were accompanied by a marked increase in the levels of Ser[Sub16]-Phoshosphorylated phospholamban (PLB). 3 In PKG I[SubTG] hearts, the effects of CNP on cardiac contractility and relaxation as well as on PLB phosphorylation were markedly enhanced. 4 CNP increased cell shortening and systolic Ca[sup2+], levels. and accelerated Ca[sup2+] decay in isolated. Indo-l/AM-loaded WT cardiomyocytes. and these effects were enhanced in PKG I-overexpressing cardiomyocytes. 5 8-pCPT-cGMP, a membrane-permeable PKG activator, mimicked the contractile and molecular actions of CNP, the effects again being more pronounced in PKG 1[subTG] hearts. In contrast, the cardiac reponses to to β-adrenergic stimulation were not different between genotypes. 6 Taken together, our data indicate that PKG is a downstream target activated by the CNP GC-B cGMP-signalling pathway in cardiac myocytes. cGMP PKG l-stinulated phosphorylation of PLB and subsequent activation of the sarcoplasmiec reliculum Ca[sup2+] pump appear to mediate the positive inotropic and lusitropic responses to CNP.
- Subjects
ATRIAL natriuretic peptides; GUANYLATE cyclase; REGULATION of heart contraction; PROTEIN kinases; CALCIUM; TRANSGENIC mice
- Publication
British Journal of Pharmacology, 2003, Vol 140, Issue 7, p1227
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0705567