Abstract 542: Blockade of Angiotensin-(1-7)-mediated Vascular Remodeling by a CB2 Cannabinoid Receptor Antagonist
Angiotensin-(1-7) [Ang-(1-7)] inhibits vascular smooth muscle cell (VSMC) growth and reduces cardiac hypertrophy and vascular remodeling in Ang II-infused hypertensive rats. We previously showed that Ang-(1-7) increased the endocannabinoid 2-AG in VSMCs and that inhibition of VSMC growth by Ang-(1-7) was prevented by blockade of CB2 cannabinoid receptors. VSMCs isolated from mice with ablated CB2 receptors were treated with platelet-derived growth factor to stimulate growth; neither Ang-(1-7) nor the CB2 receptor agonist HU308 reduced VSMC growth (98.7±9.9% and 105.4±13.0% of stimulated growth, respectively, n = 3-6), suggesting that growth inhibition by Ang-(1-7) is mediated through activation of the CB2 receptor. Ang II-infused Sprague-Dawley rats were treated for 28 days with Ang-(1-7), in the presence or absence of the CB2 receptor antagonist SR144528, to determine whether CB2 receptor blockade prevents the Ang-(1-7)-mediated reductions in Ang II-stimulated cardiac hypertrophy and vascular remodeling. Systolic blood pressure was similar in both groups, before or after treatment (115±4.6 mmHg with SR144528 and 115.7±10.2 mmHg with Ang-(1-7)/SR144528 before treatment and 186.7±6.2 mmHg and 182.0±2.1 mmHg after Ang II treatment, respectively, n=4). Ang II increased the mean cross-sectional area of cardiac myocytes which was reduced 55% by Ang-(1-7); CB2 receptor blockade prevented the Ang-(1-7)-mediated reduction in myocyte size. Fibrosis (interstitial and perivascular) and vessel size (M/L) were unchanged by Ang-(1-7) in the presence of SR144528 compared to a 79%, 85% and 90% reduction of the Ang II-mediated increase in interstitial fibrosis, perivascular fibrosis and M/L, respectively, by Ang-(1-7) alone. Brain natriuretic peptide and atrial natriuretic peptide also were unchanged by Ang-(1-7) in the hearts of rats treated with Ang II and SR144528 compared to a 91% and 99% reduction by Ang-(1-7) in Ang II-treated rats. Thus, treatment with a CB2R antagonist blunts the anti-hypertrophic and anti-fibrotic responses to Ang-(1-7) in hypertensive Ang II-treated rats, independent of blood pressure, suggesting that the growth inhibitory properties of Ang-(1-7) involve a novel pathway which includes activation of the CB2 receptor.
Author Disclosures: E. Tallant: None. A.C. Howlett: None. P.E. Gallagher: None.
- © 2014 by American Heart Association, Inc.