C2238 atrial natriuretic peptide molecular variant is associated with endothelial damage and dysfunction through natriuretic peptide receptor C signaling
Articolo
Data di Pubblicazione:
2013
Citazione:
C2238 atrial natriuretic peptide molecular variant is associated with endothelial damage and dysfunction through natriuretic peptide receptor C signaling / S. Sciarretta, S. Marchitti, F. Bianchi, A. Moyes, E. Barbato, S. Di Castro, R. Stanzione, M. Cotugno, L. Castello, C. Calvieri, I. Eberini, J. Sadoshima, A.J. Hobbs, M. Volpe, S. Rubattu. - In: CIRCULATION RESEARCH. - ISSN 0009-7330. - 112:10(2013 May 10), pp. 1355-1364.
Abstract:
Rationale: C2238 atrial natriuretic peptide (ANP) minor allele (substitution of thymidine with cytosine in position 2238) associates with increased risk of cardiovascular events. Objective: We investigated the mechanisms underlying the vascular effects of C2238-αANP. Methods and Results: In vitro, human umbilical vein endothelial cell were exposed to either wild-type (T2238)- or mutant (C2238)-αANP. Cell survival and apoptosis were tested by Trypan blue, annexin V, and cleaved caspase-3 assays. C2238-αANP significantly reduced human umbilical vein endothelial cell survival and increased apoptosis. In addition, C2238-αANP reduced endothelial tube formation, as assessed by matrigel. C2238-αANP did not differentially modulate natriuretic peptide receptor (NPR)-A/B activity with respect to T2238-αANP, as evaluated by intracellular cGMP levels. In contrast, C2238-αANP, but not T2238-αANP, markedly reduced intracellular cAMP levels in an NPR-C-dependent manner. Accordingly, C2238-αANP showed higher affinity binding to NPR-C, than T2238-αANP. Either NPR-C inhibition by antisense oligonucleotide or NPR-C gene silencing by small interfering RNA rescued survival and tube formation of human umbilical vein endothelial cell exposed to C2238-αANP. Similar data were obtained in human aortic endothelial cell with NPR-C knockdown. NPR-C activation by C2238-αANP inhibited the protein kinase A/Akt1 pathway and increased reactive oxygen species. Adenovirusmediated Akt1 reactivation rescued the detrimental effects of C2238-αANP. Overall, these data indicate that C2238-αANP affects endothelial cell integrity through NPR-C-dependent inhibition of the cAMP/protein kinase A/Akt1 pathway and increased reactive oxygen species production. Accordingly, C2238-αANP caused impairment of acetylcholine-dependent vasorelaxation ex vivo, which was rescued by NPR-C pharmacological inhibition. Finally, subjects carrying C2238 minor allele showed early endothelial dysfunction, which highlights the clinical relevance of our results. Conclusions: C2238-αANP reduces endothelial cell survival and impairs endothelial function through NPR-C signaling. NPR-C targeting represents a potential strategy to reduce cardiovascular risk in C2238 minor-allele carriers.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Akt ; T2238C gene variant ; atrial natriuretic peptide ; endothelial dysfunction ; natriuretic peptide receptor type C ; Alleles ; Aorta ; Apoptosis ; Atrial Natriuretic Factor ; Cell Survival ; Cells, Cultured ; Cyclic AMP ; Cyclic AMP-Dependent Protein Kinases ; Cyclic GMP ; Endothelium, Vascular ; Genetic Variation ; Humans ; Natriuretic Peptide, C-Type ; Proto-Oncogene Proteins c-akt ; Reactive Oxygen Species ; Signal Transduction ; Umbilical Veins
Elenco autori:
S. Sciarretta, S. Marchitti, F. Bianchi, A. Moyes, E. Barbato, S. Di Castro, R. Stanzione, M. Cotugno, L. Castello, C. Calvieri, I. Eberini, J. Sadoshima, A.J. Hobbs, M. Volpe, S. Rubattu
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