Abstract
Atherosclerosis can be induced by the injection of a gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 (PCSK9)–encoding adeno-associated viral vector (AAVmPCSK9), avoiding the need for knockout mice models, such as low-density lipoprotein receptor deficient mice. As regression of atherosclerosis is a crucial therapeutic goal, we aimed to establish a regression model based on AAVmPCSK9, which will eliminate the need for germ-line genetic modifications. C57BL6/J mice were injected with AAVmPCSK9 and were fed with Western diet for 16 weeks, followed by reversal of hyperlipidemia by a diet switch to chow and treatment with a microsomal triglyceride transfer protein inhibitor (MTPi). Sixteen weeks following AAVmPCSK9 injection, mice had advanced atherosclerotic lesions in the aortic root. Surprisingly, diet switch to chow alone reversed hyperlipidemia to near normal levels, and the addition of MTPi completely normalized hyperlipidemia. A six week reversal of hyperlipidemia, either by diet switch alone or by diet switch and MTPi treatment, was accompanied by regression of atherosclerosis as defined by a significant decrease of macrophages in the atherosclerotic plaques, compared to baseline. Thus, we have established an atherosclerosis regression model that is independent of the genetic background.
Highlights
Induction of hypercholesterolemia and atherosclerosis in animal models has provided critical insights in the pathogenesis of atherosclerosis [1, 2]
The increase in proprotein convertase subtilisin/kexin type 9 (PCSK9) resulted in a decrease in low-density lipoprotein (LDL) receptor expression in the liver (Fig 1B) and an increase in plasma cholesterol levels in mice maintained on a regular chow diet (Fig 1C)
In the present study we found that reversal of AAVmPCSK9-induced hyperlipidemia by diet switch to chow, with or without treatment with an microsomal triglyceride transfer protein (MTP) inhibitor, leads to the regression of atherosclerosis as assessed by the percentage of macrophages in the plaques
Summary
Induction of hypercholesterolemia and atherosclerosis in animal models has provided critical insights in the pathogenesis of atherosclerosis [1, 2]. Though most studies are focused on the progression of atherosclerosis and its prevention, the more common clinical setting is of a middle-aged patient that already has a substantial burden of atherosclerosis, making the ideal goal of therapy the induction of atherosclerosis regression. Atherosclerotic plaque regression can be determined in several ways, including reduction in plaque size, plaque cholesterol content, or a decreased inflammatory component as assessed by a reduction in plaque macrophage number/percentage.[3]. We have considered atherosclerosis regression to be the decrease in plaque macrophages content.
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