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Review
. 2008 May 1:13:3621-36.
doi: 10.2741/2954.

Atherosclerosis as a disease of failed endogenous repair

Andrey G Zenovich  1 , Doris A Taylor
Affiliations
Review

Atherosclerosis as a disease of failed endogenous repair

Andrey G Zenovich et al. Front Biosci. .

Abstract

As coronary artery disease (CAD) continues to be the primary cause of mortality, a more in-depth understanding of pathophysiology and novel treatments are being sought. The past two decades have established inflammation as a driving force behind CAD--from endothelial dysfunction to heart failure. Recent advances in stem/progenitor cell biology have led to initial applications of progenitor cells in CAD continuum and have revealed that atherosclerosis is, at least in part, a disease of failed endogenous vascular repair. Several key progenitor cell populations including endothelial progenitor cells (AC133+/CD34+ population), vascular progenitors (CD31+/CD45(low) population), KDR+ cells and other bone marrow subtypes are mobilized for vascular repair. However, age and risk factors negatively impact these cells even prior to clinical CAD. Sex-based differences in progenitor cell capacity for repair have emerged as a new research focus that may offer mechanistic insights into clinical CAD discrepancies between men and women. Quantifying injury and cell-based repair and better defining their interactions should enable us to halt or even prevent CAD by enhancing the repair side of the repair/injury equation.

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Figures

Figure 1
Figure 1
Schematic representation of interactions between injury and endogenous repair processes. Vascular injury generates a Th1-type inflammatory response that triggers recruitment of cells (“detrimental” progenitors, in red) leading to tissue damage. Concurrently, cells that can mediate repair and renewal of the endothelium (“reparative” progenitors, in green) are mobilized reflecting endogenous repair. This reparative pathway is mediated by Th2-type cytokines. Ultimately, the availability and functional capacity of these “reparative” progenitor cell populations declines, Th1-type inflammatory response predominates and tissue damage is perpetuated leading to lesion progression. See text for a complete discussion. Abbreviations: Th, T-helper.
Figure 2
Figure 2
Changes in aortic plaque burden and bone marrow progenitor cell populations in atherosclerotic apolipoprotein E knockout male and female mice with aging. Panel A represents mean aortic plaque burden, panel B shows mean bone marrow vascular progenitor cells (VPCs, defined as the CD31+/CD45low population), panel C reflects mean bone marrow CD34+ cells, panel D illustrates mean bone marrow endothelial progenitor cells (EPCs, defined as the AC133+/CD34+ population). Young, adolescent and middle ages correspond to 14, 21 and 32 weeks. * indicates statistical significance with p≤0.05 (comparisons between males and females).
Figure 3
Figure 3
Representative en face aortic preparations stained with Oil red O to visualize lipid deposition and plaque burden. Panel A: males treated with vehicle (left) or with male (upper right) or female (lower right) bone marrow mononuclear cells. Panel B: females treated with vehicle (left) or with male (upper right) or female (lower left) bone marrow mononuclear cells. Exact counts (and proportions, %) of animals per group that improved, did not change, or worsened after cell therapy, are shown to the right of the corresponding en face aortic preparations. Abbreviation: CI, confidence interval.
Figure 4
Figure 4
Rose-of-wind diagrams of fold differences in cytokine concentration after four bi-weekly administrations of male or female bone marrow mononuclear cells to male (panel A) and female (panel B) atherosclerotic apolipoprotein E knockout mice starting at 14 weeks of age. Th1-type cytokines are presented clockwise from MIP-1α to IL-1β, Th2-type cytokines follow from MCP-1 to IL-4, and hematopoietic/regulatory cytokines (from IL-17 to G-CSF) conclude the diagram. Abbreviations: G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; IL, interleukin; INF-γ, interferon gamma; IP, (interferon-gamma) inducible protein; KC, mouse equivalent of human IL-8; MCP-1, monocyte chemoattractant protein-1; MIP-1α, macrophage inducible protein-1 alpha; TNF-α, tumor necrosis factor alpha.
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