Abstract
Unstable atherosclerotic plaques frequently show plaque angiogenesis which increases the chance of rupture and thrombus formation leading to infarctions. Hypoxia plays a role in angiogenesis and inflammation, two processes involved in the pathogenesis of atherosclerosis. We aim to study the effect of resolution of hypoxia using carbogen gas (95% O2, 5% CO2) on the remodeling of vein graft accelerated atherosclerotic lesions in ApoE3*Leiden mice which harbor plaque angiogenesis. Single treatment resulted in a drastic decrease of intraplaque hypoxia, without affecting plaque composition. Daily treatment for three weeks resulted in 34.5% increase in vein graft patency and increased lumen size. However, after three weeks intraplaque hypoxia was comparable to the controls, as were the number of neovessels and the degree of intraplaque hemorrhage. To our surprise we found that three weeks of treatment triggered ROS accumulation and subsequent Hif1a induction, paralleled with a reduction in the macrophage content, pointing to an increase in lesion stability. Similar to what we observed in vivo, in vitro induction of ROS in bone marrow derived macrophages lead to increased Hif1a expression and extensive DNA damage and apoptosis. Our study demonstrates that carbogen treatment did improve vein graft patency and plaque stability and reduced intraplaque macrophage accumulation via ROS mediated DNA damage and apoptosis but failed to have long term effects on hypoxia and intraplaque angiogenesis.
Highlights
Thestability of atherosclerotic plaques determines the incidence of major cardiovascular events such as myocardial infarction and stroke [1]
The results of the present study show that carbogen treatment in an acute short term setting resulted in a profound reduction of intraplaque hypoxia in murine vein grafts lesions in vivo
Long term treatment with carbogen resulted in a beneficial effect on vein graft patency in ApoE3*Leiden mice, but surprisingly, had no effect on hypoxia, intraplaque angiogenesis and intraplaque hemorrhage
Summary
The (in)stability of atherosclerotic plaques determines the incidence of major cardiovascular events such as myocardial infarction and stroke [1]. Lack of oxygen within the plaque, or intraplaque hypoxia, has been identified as one of the major contributors to plaque instability [2,3]. Hypoxia, prevents degradation of Hif1a, promoting its dimerization with the Hif1b subunit This complex activates the transcription of multiple genes, the most important being Vegfa, that triggers the formation of neovessels in the plaque. Hypoxia upregulates the expression of transcription factors that cause vascular calcification in vascular smooth muscle cells [9], a characteristic feature of atherosclerosis. Both intraplaque neovessels and vascular calcification are regulated by hypoxia [9] and contribute to plaque instability. It has been shown that hypoxia can influence gene expression in macrophages, leading to an inflammatory response with increased production of pro-inflammatory cytokines [13,14]
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