Mechanistic target of rapamycin in regulating macrophage function in inflammatory cardiovascular diseases

The mechanistic target of rapamycin (mTOR) is evolutionarily conserved from yeast to humans and is one of the most fundamental pathways of living organisms. Since its discovery three decades ago, mTOR has been recognized as the center of nutrient sensing and growth, homeostasis, metabolism, life span, and aging. The role of dysregulated mTOR in common diseases, especially cancer, has been extensively studied and reported. Emerging evidence supports that mTOR critically regulates innate immune responses that govern the pathogenesis of various cardiovascular diseases. This review discusses the regulatory role of mTOR in macrophage functions in acute inflammation triggered by ischemia and in atherosclerotic cardiovascular disease (ASCVD) and heart failure with preserved ejection fraction (HFpEF), in which chronic inflammation plays critical roles. Specifically, we discuss the role of mTOR in trained immunity, immune senescence, and clonal hematopoiesis. In addition, this review includes a discussion on the architecture of mTOR, the function of its regulatory complexes, and the dual-arm signals required for mTOR activation to reflect the current knowledge state. We emphasize future research directions necessary to understand better the powerful pathway to take advantage of the mTOR inhibitors for innovative applications in patients with cardiovascular diseases associated with aging and inflammation.

Automated summary

mTOR, a mechanistic target of rapamycin, is an evolutionarily conserved pathway that plays a fundamental role in nutrient sensing, growth, metabolism, lifespan, and aging. Recent studies have highlighted the regulatory role of mTOR in innate immune responses and its involvement in the pathogenesis of cardiovascular diseases, especially in acute inflammation and atherosclerotic cardiovascular disease. This review also discusses mTOR's role in trained immunity, immune senescence, and clonal hematopoiesis, as well as its architecture and regulatory complexes.