Anti-hypertrophic effects of oxytocin in rat ventricular myocytes.
BACKGROUND
Oxytocin (OT) and functional OT receptor (OTR) are expressed in the heart and are involved in blood pressure regulation and cardioprotection. Cardiac OTR signaling is associated with atrial natriuretic peptide (ANP) and nitric oxide (NO) release. During the synthesis of OT, its precursor, termed OT-Gly-Lys-Arg (OT-GKR), is accumulated in the developing rat heart. Consequently, we hypothesized that an OT-related mechanism of ANP controls cardiomyocyte (CM) hypertrophy.


METHODS
The experiments were carried out in newborn and adult rat CM cultures. The enhanced protein synthesis and increased CM volume were mediated by a 24-h treatment with endothelin-1 or angiotensin II.


RESULTS
The treatment of CM with OT or its abundant cardiac precursor, OT-GKR, revealed ANP accumulation in the cell peri-nuclear region and increased intracellular cGMP. Consequently, the CM hypertrophy was abolished by the treatment of 10nM OT or 10nM OT-GKR. The ANP receptor antagonist (anantin) and NO synthases inhibitor (l-NAME) inhibited cGMP production in CMs exposed to OT. STO-609 and compound C inhibition of anti-hypertrophic OT effects in CMs indicated the contribution of calcium-calmodulin kinase kinase and AMP-activated protein kinase pathways. Moreover, in ET-1 stimulated cells, OT treatment normalized the reduced Akt phosphorylation, prevented abundant accumulation of ANP and blocked ET-1-mediated translocation of nuclear factor of activated T-cells (NFAT) into the cell nuclei.


CONCLUSIONS
cGMP/protein kinase G mediates OT-induced anti-hypertrophic response with the contribution of ANP and NO. OT treatment represents a novel approach in attenuation of cardiac hypertrophy during development and cardiac pathology.
Cardiovascular Biochemistry Laboratory, CRCHUM, Department of Medicine, University of Montreal Quebec, Canada.
Ahmed
A
Menaouar
Cardiovascular Biochemistry Laboratory, CRCHUM, Department of Medicine, University of Montreal Quebec, Canada.
Maria
M
Florian
Cardiovascular Biochemistry Laboratory, CRCHUM, Department of Medicine, University of Montreal Quebec, Canada.
Donghao
D
Wang
Cardiovascular Biochemistry Laboratory, CRCHUM, Department of Medicine, University of Montreal Quebec, Canada.
Bogdan
B
Danalache
Cardiovascular Biochemistry Laboratory, CRCHUM, Department of Medicine, University of Montreal Quebec, Canada.
Marek
M
Jankowski
Cardiovascular Biochemistry Laboratory, CRCHUM, Department of Medicine, University of Montreal Quebec, Canada.
Jolanta
J
Gutkowska
D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000188:drug therapy / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D049108:Cell Enlargement / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010121:Oxytocin / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D010121:Oxytocin
Atrial natriuretic peptide; Cardiac myocytes; Cyclic GMP; Endothelin 1; Hypertrophy; Oxytocin