mTOR and vascular remodeling in lung diseases: current challenges and therapeutic prospects.
Mammalian target of rapamycin (mTOR) is a major regulator of cellular metabolism, proliferation, and survival that is implicated in various proliferative and metabolic diseases, including obesity, type 2 diabetes, hamartoma syndromes, and cancer. Emerging evidence suggests a potential critical role of mTOR signaling in pulmonary vascular remodeling. Remodeling of small pulmonary arteries due to increased proliferation, resistance to apoptosis, and altered metabolism of cells forming the pulmonary vascular wall is a key currently irreversible pathological feature of pulmonary hypertension, a progressive pulmonary vascular disorder with high morbidity and mortality. In addition to rare familial and idiopathic forms, pulmonary hypertension is also a life-threatening complication of several lung diseases associated with hypoxia. This review aims to summarize our current knowledge and recent advances in understanding the role of the mTOR pathway in pulmonary vascular remodeling, with a specific focus on the hypoxia component, a confirmed shared trigger of pulmonary hypertension in lung diseases. We also discuss the emerging role of mTOR as a promising therapeutic target and mTOR inhibitors as potential pharmacological approaches to treat pulmonary vascular remodeling in pulmonary hypertension.
University of Pennsylvania Perelman School of Medicine, Translational Research Laboratories, Rm. 1214, 125 South 31st St., Philadelphia, PA 19104, USA. goncharo@mail.med.upenn.edu
Elena A
EA
Goncharova
D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008168:Lung / Q000098:blood supply*; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D011651:Pulmonary Artery / Q000503:physiopathology; D011652:Pulmonary Circulation; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D014652:Vascular Diseases / Q000503:physiopathology
D015220:Calcium Channels; D036341:Intercellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus