Crippling Cardiovascular Disease With Kruppels

Abstract

The metabolic and immune systems are evolutionary conserved, highly interdependent, and requisite for survival. Dysfunction of either system alters homeostasis and contributes to cardiovascular disease, cancer, and metabolic disorders. Studies from our laboratory have identified an essential role for a family of transcription factors termed Kruppel-like factors (KLFs) in innate immunity, metabolism, and the cardiovascular response to physiologic and pathologic stimuli. Mechanistically, this work has led to an appreciation of how KLFs intersect with nodal transcriptional and epigenetic pathways to exact their biological action. Here, I will first review how control of cellular inflammation and metabolism by KLFs impacts key steps in the pathogenesis of vascular disease, including endothelial dysfunction, immune cell activation, smooth muscle proliferation, and thrombosis. Next, I will discuss how KLFs coordinate systemic metabolic homeostasis by controlling flux of all three major cellular nutrient classes — glucose, amino acids, and lipids — observations that provide insights as to how diverse physiologic stimuli such as fasting, circadian rhythms, and exercise impact health. Finally, I will highlight the evidence linking KLFs to human disease and how these observations along with mechanistic insights are being exploited for therapeutic gain.