Abstract 14201: Vasopressin Type 1a Receptor Deficiency Prevents the Onset of Heart Failure: Possible Link with Myocardial Fibrosis
Background: Plasma arginine vasopressin (AVP) levels are increased and correlated with adverse outcome in heart failure (HF). Among the three distinct receptor subtypes: V1a, V1b, and V2 receptors, V1a receptors (V1aR) are abundantly expressed in the myocardium and reported to exert vosoconstrictive, positive inotropic, or mitogenic actions. However, the long-term effects of V1aR disruption on in vivo myocardium during cardiac stress are still unclear. Therefore, we utilized the mice lacking V1aR, which showed a similar baseline phenotype as wild-type (WT) mice, and clarified the role of V1aR during cardiac hypertrophy and HF.
Methods and Results: V1aR knockout (KO) mice (n=8) and WT controls (n=8) were infused with angiotensin II (Ang II) (2ug/kg/min) for 2 weeks. V1aR KO mice exhibited less myocardial fibrosis (fibrotic area; 2.7%) than WT mice (9.5%) and slightly lowerd left ventricular weight (LVW) / tibial length (TL) ratios. Concomitantly, expression of connective tissue growth factor, collagens, and periostin was significantly suppressed in V1aR KO mice. However, expression of the hypertrophic markers: α-skeletal actin, βMHC, and ANF in LV were not different. Additionally, transverse aortic constriction (TAC) was performed in V1aR KO (n=28) and WT mice (n=30). In WT mice, LV function was disturbed and signs of HF observed at 8 weeks after TAC. V1aR KO mice showed decreased LVW/TL ratio (p=0.037) and preserved LV function at 8 weeks after TAC (fractional shortening; 45.8% in KO vs 29.3% in WT, p<0.001). Pulmonary congestion was prevented and increase of BNP mRNA and decrease of SERCA2a mRNA were significantly suppressed (p<0.01) in V1aR KO mice. Myocardial fibrosis was significantly suppressed in KO mice (fibrotic area; 3.1% in KO vs 8.4% in WT), but the hypertrophic markers were identical between the groups.
Conclusions: V1aR activation contributes to the profibrotic effect of Ang II in the heart as well as the fibrosis seen in acute pressure-overloaded LV. Consequently, V1aR deficiency prevents the onset of HF independent of suppressing myocyte hypertrophy. Chronic blockade of V1aR may have therapeutic potential in human HF by attenuating myocardial fibrosis, at least in part by intercepting a downstream effect of Ang II.
- © 2010 by American Heart Association, Inc.