Arterial contractility and blood pressure regulation by statins - PROJECT SUMMARY: Statins are used by over 200 million people worldwide for treating atherosclerotic cardiovascular diseases such as hypertension, coronary artery disease, and stroke. Pre-clinical and clinical data suggest that statins produce blood pressure (BP)-lowering action in some subjects while having BP-neutral effects in others. However, the underlying mechanism for such contrasting effects remains unclear. The conventional view is that long-term statin therapy produces a range of beneficial vascular effects due to the inhibition of mevalonate/cholesterol biosynthesis and Rho and Rho-associated protein kinase (ROCK) signaling in vascular smooth muscle cells (SMCs) and endothelial cells (ECs). However, whether statins can directly act on a vascular target to regulate arterial contractility, independent of the conventional pathways, and the pathophysiological significance of such a target of direct statin action remain unclear. Due to the coexistence of hypertension and dyslipidemia and the use of statins by over 200 million people, it is critically important to determine whether statins have inherent BP-lowering actions so that clinicians can tailor antihypertensive therapy to the needs of individual patients. In this proposal, we aim to investigate the direct vascular effects of the three most commonly used statins in resistance mesenteric arteries (RMAs) from wild-type and transgenic normotensive and hypertensive animals to determine the mechanism of differential BP regulation by statins, both acutely and in the long- term, and propose a framework for harnessing the BP-lowering actions of statins that may potentially benefit millions. Based on our novel preliminary data, the central hypothesis of this proposal is that statins stimulate rapid RMA vasodilation by selectively inhibiting phosphodiesterase 1A (PDE1A) in SMCs, thereby elevating [cGMP]i, leading to protein kinase G (PKG) activation, vasodilation, and BP reduction, an effect that is abolished by endothelial dysfunction that impairs upstream NO signaling into SMCs. In this proposal, we will to characterize the role of the NO- PDE1A/cGMP-PKG signaling axis, which may shed light on the mechanisms behind BP-lowering and BP-neutral effects of statins. Overall, this proposal could unveil novel cardiovascular targets and therapeutic applications of the world’s most prescribed drugs in hypertension, and serve as the guide to clinicians to tailor antihypertensive therapy to the individual needs of patients with coexisting hypertension and dyslipidemia.
