Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart's adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure.

The role of inflammation in vascular disease is well recognized, involving dysregulation of both circulating immune cells as well as the cells of the vessel wall itself. Unrestrained vascular inflammation leads to pathological remodeling that eventually contributes to atherothrombotic disease and its associated sequelae (e.g., myocardial/cerebral infarction, embolism, and critical limb ischemia). Signaling events during vascular inflammation orchestrate widespread transcriptional programs that affect the functions of vascular and circulating inflammatory cells. The Krüppel-like factors (KLFs) are a family of transcription factors central in regulating vascular biology in states of homeostasis and disease. Given their abundance and diversity of function in cells associated with vascular inflammation, understanding the transcriptional networks regulated by KLFs will further our understanding of the pathogenesis underlying several pervasive health concerns (e.g., atherosclerosis, stroke, etc.) and consequently inform the treatment of cardiovascular disease. Within this review, we will discuss the role of KLFs in coordinating protective and deleterious responses during vascular inflammation, while addressing the potential targeting of these critical transcription factors in future therapies.

(1), where M. tuberculosis persists as an intracellular pathogen harbored by macrophages. Infection of alveolar and tissue-resident macrophages leads to engagement of innate immune receptors by pathogen-derived molecules and activates macrophage responses that help contain the infection (2, 3) but fail to eradicate it. T helper type 1 (Th1) responses and the production of interferon gamma (IFN-␥) are particularly important to the containment of M. tuberculosis infection (4-6), but T cells exhibit delayed responses in the lung and do not provide sterilizing immunity (7-10). Effector T cells may exhibit plasticity in their Th1 polarization due to effects of the lung microenvironment (11-13).M. tuberculosis possesses mechanisms to interfere with host immunity and establish latent infection, enabling it to persist primarily within macrophages in lung granulomas (14). Some immune evasion mechanisms affect macrophage functions; examples are interference with macrophage microbicidal responses, such as reactive oxygen and reactive nitrogen intermediates (15, 16); suppression of class II major histocompatibility complex (MHC-II) expression and, hence, presentation of antigens to CD4 ϩ T cells (17-21); and regulation of cytokines expressed by macrophages, e.g., the induction of interleukin-10 (IL-10), which has immune-suppressive functions (22-24). Regulation of some macrophage functions, such as cytokine and MHC expression,