Advisory Committee Chair
Sumanth D Prabhu
Advisory Committee Members
Martin Young
Lesley Smythies
Robinna Lorenz
James George
Document Type
Dissertation
Date of Award
2017
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Cardiac pressure-overload is a state of increased hemodynamic load and is initially characterized by concentric left ventricular (LV) hypertrophy, but can transition to eccentric hypertrophy and adverse LV remodeling leading to heart failure (HF). Cardiac remodeling during pressure-overload is accompanied by dysregulated collagen deposition, cardiomyocyte hypertrophy, and increased inflammatory signaling. Both clinical and preclinical studies have documented increased expression of inflammatory cytokines and leukocyte infiltration in the pressure-overloaded heart, indicating inflammatory mechanisms are active during cardiac remodeling. Despite the well-known link between leukocyte infiltration and exacerbated tissue injury, the role of innate immune cells, particularly monocytes, macrophages and dendritic cells, in the pressure-overloaded myocardium is unclear. We hypothesized that macrophages are indispensable for cardiac remodeling induced by pressure-overload. Using the transverse aortic constriction (TAC) model of pressure overload, we first show there is a phasic expansion of Ly6Chi circulating monocytes, pro-inflammatory CD206- cardiac macrophages, and CD11c+ dendritic cells in TAC mice. Secondly, using pharmacological targeting of C-C chemokine receptor 2 (CCR2), we demonstrate that the source of increased cardiac macrophages during acute pressure overload is primarily monocyte-derived infiltrating macrophages. Finally, we provide evidence that infiltrating macrophages are necessary for the development of LV fibrosis, cardiac hypertrophy and T-cell recruitment during chronic pressure-overload HF. We conclude infiltrating macrophages are fundamental mediators of cardiac remodeling during pressure-overload, and serve as a potential therapeutic target to delay or prevent the transition to HF.
Recommended Citation
Patel, Bindiya Dinesh, "The Role of Macrophages in Pressure-Overload Induced Cardiac Remodeling" (2017). All ETDs from UAB. 2672.
https://digitalcommons.library.uab.edu/etd-collection/2672