Mineralocorticoids have an important function during normal physiology, but increased mineralocorticoid receptor (MR) activation can cause or exacerbate a variety of diseases. Stroke is a major cause of mortality, and MR activation has a detrimental effect during ischemic stroke. MR antagonists provide beneficial effects during models of ischemic stroke independent of their blood pressure-lowering effects. We have recently shown that myeloid cells are critical targets for MR antagonists during ischemic stroke. However, cell-type- specific contribution of different myeloid cells and the mechanism by which myeloid MR exacerbates stroke is still unknown. Our laboratory has demonstrated that MR activation enhances pro-inflammatory, classical macrophage activation, whereas MR antagonism results in anti-inflammatory, alternative macrophage activation. We hypothesize that changes in macrophage activation are important in controlling the inflammatory component of stroke. The proposed studies will identify the cell-type-specific contributions and seek to identif the mechanisms by which myeloid MR activation exacerbates ischemic stroke. Furthermore, we will test whether we can enhance alternative macrophage activation with pharmacological synergy to provide additional neuroprotection during stroke.
Our long-term goal is to delineate the mechanisms by which myeloid mineralocorticoid receptor (MR) exacerbates ischemic stroke, and to understand the role that MR regulation of macrophage polarization has during stroke. My proposed studies will help provide an understanding of the regulation of macrophage phenotypes during stroke and identify ways in which we can alter these phenotypes with pharmacological interventions.
|Frieler, Ryan A; Mortensen, Richard M (2015) Immune cell and other noncardiomyocyte regulation of cardiac hypertrophy and remodeling. Circulation 131:1019-30|
|Li, Chao; Zhang, Yu Yao; Frieler, Ryan A et al. (2014) Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice. PLoS One 9:e110950|
|Frieler, Ryan A; Ray, Jessica J; Meng, He et al. (2012) Myeloid mineralocorticoid receptor during experimental ischemic stroke: effects of model and sex. J Am Heart Assoc 1:e002584|