Abstract P231: Lipoprotein Lipase Activation Is A Novel Anti-contractile Mechanism That Is Both Endothelium-dependent And Independent.

Abstract

Risk factors such as hypertriglyceridemia and hypercholesterolemia are commonly attributed to the pathogenesis of atherosclerosis, however, lipoprotein metabolism is also associated with end organ damage and cardiovascular events in hypertensive patients. Lipoprotein lipase (LPL) is an important hydrolase for lipoprotein catabolism. Previous work from our lab has shown that LPL activator, NO-1886 (Ibrolipim), significantly decreased vascular contraction. Physiologically, endothelial function limits contractility and endothelial dysfunction is a hallmark of hypertension. Therefore, we hypothesized that LPL activation would cause endothelial-dependent hypocontractility. To test this hypothesis, mesenteric resistance arteries (MRA) were isolated from male Fischer 344 rats at 3 months of age (n=4-12) and mounted onto a wire myograph. Phenylephrine (PE) concentration-response curves were performed with and without LPL activator, NO-1886 (30 min). Some MRA were denuded of their endothelium or incubated with inhibitors of endothelium-dependent vasodilation. As expected, activating LPL exerted a significant anti-contractile effect in a concentration-dependent manner [KCl (%), Veh: 125±3 vs. NO-1886 (1 uM): 116.0±17 vs. NO-1886 (10 uM): 108±9* vs. NO-1886 (50 uM): 55±4* vs. NO-1886 (100 uM): 29±5*, *p<0.05 vs. Veh]. However, contrary to our hypothesis, denudation only partially restored contraction [KCl (%),Veh: 125±3 vs. NO-1886 (50 uM): 55±4* vs. NO-1886+denuded: 76±4* # , *p<0.05 vs. Veh, # p<0.05 vs. NO-1886]. This suggests that there is both an endothelium-dependent and -independent mechanism by which LPL limits contractility. Endothelial-dependent hypocontractility was found to be mediated by nitric oxide synthase [KCl (%),Veh: 125±3 vs. NO-1886 (50 uM): 55±4 vs. NO-1886+L-NAME (100 uM): 90±5* # , *p<0.05 vs. Veh, # p<0.05 vs. NO-1886]. Endothelium-independent mechanisms by which NO-1886 causes hypocontractility have yet been clarified (data not shown). Overall, this suggests that LPL has an important physiological role in controlling vascular contraction through both endothelial-dependent and -independent means and loss of LPL activity could be a novel mechanism of endothelial dysfunction in hypertension.