Abstract 11409: Kappa-opioid Stimulation Following Chronic Cardiac Pressure Overload Increases Endothelial Caveolae Formation and Benefits Cardiac Function
Activation of kappa (κ) -opioid receptors (OR) protects from cardiac ischemia reperfusion injury. A critical role for caveolae in opioid mediated cardio-protection has been shown but these findings have not extended beyond the myocyte. The rationale here was to test if chronic κ- OR activation ameliorates pressure overload induced heart failure after transverse aortic constriction (TAC) and determine potential molecular mechanisms. Ten week-old male C57BL/6J mice underwent TAC or Sham surgery. Cardiac function was assessed by echocardiography before TAC/Sham, and consecutively at weeks 2, 4, 6, 8 and 10 to determine cardiac function (%EF), and wall thicknesses (LVPWd). Two weeks after TAC/Sham, daily i.p. injections with a selective κ-OR, U50488H (U50, TOCRIS®, 1.25mg/kg, IP), or vehicle (V, ddH2O) were started. Eleven weeks post-TAC (pTAC), hearts were analyzed by transmission electron microscopy (TEM, n=2 each) and immuohistochemistry (n=4 each). Four weeks pTAC LVPWd in TAC+U50 mice were increased compared to TAC+V, and %EF unchanged (mm±SEM; Sham+V 0.67±0.01, TAC+V 0.81±0.02, Sham+U50 0.66±0.01,TAC+U50 0.93±0.03, n=6-7, p <0.007). Ten weeks pTAC %EF was reduced in TAC+V compared to Sham+V, but preserved in TAC+U50 hearts compared to Sham+U50 (%EF±SEM; Sham+V 68.9%±1, TAC+V 49.5%±8; Sham+U50 73.6%±1.7,TAC+U50 65.3%±6, ns; p<0.02; n=6-7each). Eleven weeks pTAC, TEM revealed preserved mitochondrial utrastructure, and electron dense intercalated discs in pTAC+U50 animals. TAC+V hearts showed “bleached” intercalated discs and swollen mitochondria. U50 increased endothelial caveolae formation in Sham+U50 and TAC+U50 hearts (Cav/μm, 13.3 fold upregulation in Sham+U50 vs Sham+V; and a 3.7 fold increase in TAC+U50 vs TAC+V, p<0.004, 15 cells/heart). Immunohistochemical analysis revealed intracellular accumulation of connexin-43 in TAC+V treated mice, but connexin-43 localization was preserved to membranes in TAC+U50 hearts. We show for the first time that chronic κ-OR activation via U50,488H increased caveolae formation in cardiac endothelial cells, improved cardiac ultrastructure and prevented pressure overload induced heart failure. U50,488H administration may offer a novel treatment option in patients prone to heart failure.
Author Disclosures: A.E. Zemljic-Harpf: None. D.N. Deussen: None. M.A. Joshi: None. B.F. Alas: None. Y.J. Vainshnav: None. S.K. Mahata: None. D.M. Roth: None. H.H. Patel: None.
- © 2016 by American Heart Association, Inc.