It is well known that antagonists of mineralocorticoid receptor (MR), a classic steroid hormone receptor, are cardioprotective and anti-inflammatory.These effects can be independent of hyperaldosteronism, suggesting the possibility of direct action.Macrophage polarization has emerged as an important control element in cardiovascular diseases (CVD).We have used a mouse model of myeloid-specific deletion of MR (MMRKO) to investigate the role of myeloid MR in CVD.MMRKO skews macrophages to an alternatively activated phenotype and protects cardiac and vascular damages under pathological stress.In addition, MMRKO synergizes with other nuclear transcription factors such as Peroxisome-Proliferator-Activated-Receptor-gamma and glucocorticoid receptor to enhance alternative activation of maerophages.These studies demonstrate that myeloid MR is an important modulator of macrophage polarization and cardiovascular protection.These studies also present possibilities to develop new antagonists to target myeloid MR specifically in order to treat CVD more effectively.