Ischemic heart disease and stroke primarily result from atherosclerosis and are leading causes of mortality in the elderly. However, the reasons why the elderly are particularly susceptible to atherosclerosis and related diseases are incompletely understood. A key factor for this knowledge gap is that the vast majority of rodent studies of atherosclerosis utilize young mice. Our overall goal is to generate seminal insights into atherogenesis and thereby, devise novel strategies to reduce the heavy burden of cardiovascular diseases in the elderly. The proposed studies result from a synergistic collaboration between two investigators with complimentary expertise: Daniel Greif, M.D. (smooth muscle cell [SMC] biology, lineage and clonal analysis and cardiovascular disease) and Carlos Fernndez-Hernando, Ph.D. (lipid metabolism, vascular biology and inflammation and atherosclerosis models). Recent studies from our laboratories and other groups suggest that rare progenitors expressing SMC markers are recruited into atherosclerotic plaques and clonally expand. Indeed, our recent joint paper demonstrates that a single pre-existing SMC gives rise to the majority of all the cells in an advanced atherosclerotic plaque and that bone marrow-derived cells (presumably macrophages) regulate the recruitment and clonal expansion of SMC progenitors (Nature Communications, 2018, in press). We also demonstrate that in contrast to SMC progenitors, multiple myeloid cells are recruited into atherosclerotic plaques. A strong correlation between clonal hematopoiesis and atherosclerotic cardiovascular disease has recently been identified; however, it is not known whether there is clonal expansion of macrophages within plaques and if so, the impact of such clonal expansion. Similarly, it remains to be determined how aging influences SMC clonality and the importance of clonal hematopoiesis in regulating plaque progression. We suggest that aging has deleterious effects on the recruitment of pre-existing myeloid or SMC marker+ progenitors into atherosclerotic plaques and their clonal expansion. Our proposed studies utilize young and old transgenic mice carrying a multi-color Cre reporter and subjected to a state-of-the-art model of atherosclerosis - single injection with recombinant, replication-deficient AAV vector encoding a gain-of-function Pcsk9 transgene to reduce LDL receptor levels, followed by Western diet ? and also utilize isolated SMCs, bone marrow-derived cells and plaque cells. Our investigations have two specific aims: 1) determine effects of aging on atherosclerotic plaque burden and content and on the architecture and gene expression of clones of myeloid-derived plaque cells; and 2) elucidate effects of aging on the fate and on the architecture and gene expression of clones of SMC-derived plaque cells. The experiments delineated in this R21 proposal will yield key insights into atherogenesis and will provide the groundwork for a future R01 application investigating mechanistic underpinnings of how aging regulates clonality of atherosclerotic plaque cells derived from SMCs and myeloid cells.

Public Health Relevance

Heart attack and stroke primarily result from atherosclerosis and are the leading cause of death in the elderly. Vascular smooth muscle cells and macrophages are key contributors to atherosclerotic plaques, and herein, we evaluate underlying mechanisms. The proposed studies will enhance our understanding of the role of smooth muscle cells and macrophages in atherosclerosis and thus, facilitate the development of novel therapeutic strategies to combat this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG062202-01
Application #
9687261
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Kerr, Candace L
Project Start
2019-01-15
Project End
2020-11-30
Budget Start
2019-01-15
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520