Role of Toll-like receptor mediated signaling pathway in ischemic heart.
Stimulation of TLRs by exogenous and endogenous ligands triggers expression of several genes that are involved in innate immune responses. Recently, a role of TLR4 in the myocardial response to injury separate from microbial pathogens has been examined in experimental studies. TLR4 deficient mice sustain significantly smaller infarctions compared with wild-type control mice given similar areas at risk. Levels of serum cytokines such as IL-1b, IL-6, and TNFa are increased after ischemia/reperfusion, but these responses are attenuated in TLR4 deficient mice compared to control mice. TLR2 signaling also importantly contributes to cardiac dysfunction following ischemia/reperfusion. MyD88, a key adaptor protein for TLR signaling, is responsible for the protective effects of TLR signaling inhibition in ischemia/reperfusion injury. TLR4 gene polymorphism (Asp299Gly) attenuates innate immune responsiveness, reduces the risk for coronary artery disease, and increases a chance of longevity. The innate immune system is clearly involved in the pathogenesis of cardiovascular diseases and could be a new therapeutic target.
Takeishi
Yasuchika
Y
First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan. takeishi@fmu.ac.jp
Kubota
Isao
I
D006801:Humans; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism; D011110:Polymorphism, Genetic; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors