[Frontiers in Bioscience 14, 2553-2558, January 1, 2009]

Role of Toll-like receptor mediated signaling pathway in ischemic heart

Yasuchika Takeishi1, Isao Kubota2

1First Department of Internal Medicine, Fukushima Medical University, Fukushima, and 2Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Expressions of TLRs in the heart and vasculature
4. TLR signaling pathway
5. Role of TLR4 signaling in myocardial ischemia/reperfusion
6. Functional role of TLR2 in ischemic hearts
7. MyD88 is a key adaptor protein for TLR signaling
8. Clinical significance of TLR gene polymorphism
9. Perspective
10. Acknowledgements
11. References

1. ABSTRACT

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.