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Apolipoprotein E receptor 2 deficiency alters smooth muscle cell and macrophage characteristics to promote atherosclerotic lesion necrosis

Waltmann, Meaghan D

Abstract Details

2013, PhD, University of Cincinnati, Medicine: Pathobiology and Molecular Medicine.
Cardiovascular disease is the leading cause of death in the U.S. Atherosclerosis, a progressive, multi-factorial disease that is characterized by the accumulation of lipoprotein particles, cells, and fibrous tissue in the vascular wall, is the underlying cause of the majority of deaths related to cardiovascular disease. In the late stages of atherosclerosis, the rupturing of the atherosclerotic plaque results in the exposure of the inner constituents of the plaque to the blood and subsequent thrombosis which is the leading cause of myocardial infarction (MI) and stroke. As the atherosclerosis disease progresses, atherosclerotic plaques can develop into complex lesions that are more likely to rupture. These unstable plaques are associated with distinct morphological and histological features including increased plaque macrophages, reduced plaque smooth muscle cells (SMCs), and the formation of a necrotic core. Previous studies have shown that the low-density lipoprotein receptor (Ldlr) family of receptors plays an integral role in atherosclerosis. Genetic analyses have associated one member of this receptor family, the apolipoprotein E receptor 2 (apoER2; Gene Name: LRP8), with familial and premature coronary artery disease and MI in humans. Although this receptor is expressed by endothelial cells, SMCs, monocytes/macrophages, and platelets, the contribution of this receptor to atherosclerosis is currently unknown. The goal of this study was to determine the effect apoER2 has on atherosclerosis. Since previous studies have suggested a role for apoER2 in maintaining cell viability, we hypothesized that apoER2 deficiency would enhance atherosclerotic lesion severity through a mechanism involving reduced macrophage and smooth muscle cell viability. This study demonstrated that inactivation of the Lrp8 gene in Ldlr deficient mice (Lrp8-/- Ldlr-/-) resulted in the formation of highly necrotic complex lesions rich in macrophages and apoptotic cells, but relatively devoid of SMCs after 24 weeks on a high fat, high cholesterol Western-type diet compared to Lrp8+/+ Ldlr-/-. Consistent with the in vivo phenotype, apoER2 deficient macrophages in vitro accumulated more neutral lipids, were under increased oxidative stress, and were more susceptible to stress-induced cell death through a mechanism involving defective activation of Akt and enhanced activation of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ). Additionally, apoER2 deficient SMCs had reduced proliferative capacity, reduced viability, and were under increased oxidative stress in vitro through a mechanism involving defective activation of Akt. Taken together, these data suggest that apoER2 protects against the formation of highly necrotic, complex lesions through maintenance of macrophage and SMC viability and function.
David Hui, Ph.D. (Committee Chair)
William Sean Davidson, Ph.D. (Committee Member)
Philip Howles, Ph.D. (Committee Member)
Walter Jones, Ph.D. (Committee Member)
Neal Weintraub, M.D. (Committee Member)
135 p.

Recommended Citations

Citations

  • Waltmann, M. D. (2013). Apolipoprotein E receptor 2 deficiency alters smooth muscle cell and macrophage characteristics to promote atherosclerotic lesion necrosis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1384851103

    APA Style (7th edition)

  • Waltmann, Meaghan. Apolipoprotein E receptor 2 deficiency alters smooth muscle cell and macrophage characteristics to promote atherosclerotic lesion necrosis. 2013. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1384851103.

    MLA Style (8th edition)

  • Waltmann, Meaghan. "Apolipoprotein E receptor 2 deficiency alters smooth muscle cell and macrophage characteristics to promote atherosclerotic lesion necrosis." Doctoral dissertation, University of Cincinnati, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1384851103

    Chicago Manual of Style (17th edition)