Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY/ABSTRACT Atherosclerotic cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. Furthermore, despite aggressive lipid-lowering strategies, e.g., statins and anti-PCSK9 blocking antibodies, most individuals still suffer from recurrent myocardial infarctions and strokes. This “residual risk” has now been attributed to excessive inflammation and pathologic vascular remodeling, cellular events that alter vessel architecture, drive extracellular matrix degradation, and promote vascular calcification. While directly targeting inflammation is a challenging approach, as those receiving anti-inflammatory therapies experience a significant increase in the risk of death due to infection or sepsis, developing strategies that attenuate extracellular matrix (ECM) degradation and vascular calcification are vital to the next generation of successful cardiovascular therapeutics. However, the cellular and molecular mechanisms that drive these features of plaque instability have yet to be fully revealed. Our supporting data herein provide evidence that the polyamine biosynthetic pathway, which generates amino acid-derived small polycations, becomes dysregulated during atherosclerosis progression and that impairments in polyamine biosynthesis drive vascular smooth muscle cell (vSMC) phenotypic modulation. Ornithine decarboxylase (ODC1), the rate-limiting enzyme in polyamine synthesis, catalyzes the conversion of the amino acid ornithine into putrescine, and our new data identify a critical role for ODC1-dependent putrescine synthesis in vSMC function during atherosclerosis. We demonstrate that (1) putrescine synthesis by vSMCs decreases as atherosclerosis progresses in humans, particularly in unstable plaques, and mice, (2) impairments in putrescine synthesis lead to vSMC phenotypic modulation, and (3) vSMCs that are incapable of synthesizing putrescine show enhanced degradation of ECM proteins and increased calcium deposition, features of atherosclerosis that drive plaque instability. Accordingly, these preliminary data lead us to form the overarching hypothesis that impaired putrescine synthesis in vSMCs drives plaque destabilization by promoting phenotypic modulation, increasing ECM degradation, and enhancing vascular calcification. Based on the above premises and our extensive supporting data, we propose that impaired putrescine synthesis in vSMCs drives plaque destabilization by promoting phenotypic modulation, increasing ECM degradation, and enhancing vascular calcification. Our main objectives are to (1) define the mechanisms by which putrescine synthesis promotes vSMC differentiation, (2) determine the mechanisms by which impaired putrescine synthesis drives extracellular matrix degradation and vascular calcification in atherosclerosis, and (3) identify the mechanisms that impair putrescine synthesis in vSMCs during atherosclerosis. Successful completion of these aims will identify the mechanisms by which impairments in putrescine promote plaque instability and demonstrate that strategies to enhance putrescine synthesis in vSMCs mitigates atherosclerosis.
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