Chu-Huang Chen が研究セミナーで講演

講師：Chu-Huang Chen
Director, Vascular & Medicinal Research, Texas Heart Institute, USA
日時：令和元年9月26日（木）18：00〜19：00
場所：旭総合研究棟　修士講義室
演題：Role of the L5-LOX-1 Signalling Axis in Cardiovascular Aging

　　

発表の概要：
Atherosclerotic cardiovascular disease is a manifestation of cardiovascular aging, which progresses at a different pace from one individual to another. Although atherosclerosis can be initiated by a variety of factors, the common pathological denominator is deposition of low-density lipoprotein (LDL) in the arterial walls. Because normal LDL is health beneficial, it has long been speculated that the “culprit” LDL subtype differs from normal LDL constitutionally. Both oxidized LDL and small-dense LDL are considered atherogenic for a number of reasons but neither has been isolated from circulation for chemical or functional scrutiny. In contrast, electronegative LDL is easily retrievable from the plasma. Through anion-exchange chromatography, human LDL can be divided into 5 subfractions, L1-L5, with L5 being the most electronegative. By comparison, L1 is the least electronegative subfraction, which represents the majority of LDL particles. Whereas L1 provides nutrition to cells, L5 induces inflammation, senescence, and apoptosis in a variety of vascular cells. Unlike L1, which is endocytosed by normal LDL receptor (LDLR),L5 is rejected by LDLR. Instead, L5 signals through lectin-like oxidized LDL receptor-1 (LOX-1), which was cloned against oxidized LDL epitopes by Dr. Tatsuya Sawamura and colleagues in the early 1990’s. In addition to L5 and oxidized LDL, LOX-1 mediates the signaling of many substances that are also negatively charged, such as C-reactiveprotein (CRP) and tumor necrosis factor alpha (TNF-α). Regardless of its ligands, LOX-1 signaling induces a spectrum of inflammatory changes in cells. Of importance, L5 is a naturally-occurring lipoprotein that not only induces expression of CRP and TNF-α in endothelial cells but also interacts with these cytokines to accentuate inflammatory reactions. In human platelets, L5 acts via LOX-1 to enhance both the expression and the effect of amyloid-beta totrigger platelet aggregation. Scarce in healthy subjects, L5 is increased in patients with cardiometabolic disorders and autoimmune states. In patients undergoing acute ischemic events, such as acute myocardial infarction and acute ischemic stroke, L5 is remarkably elevated in the circulation. Most recently, we found that both LOX-1 and its soluble fragment, sLOX-1, are increased in patients with ST-elevation myocardial infarction, in concomitance with elevation of plasma L5. LOX-1 is minimally expressed in vascular endothelial cells under normal conditions, but its expression can be significantly augmented by L5. Mechanistically, L5 induces senescence of arterial endothelial cells by disrupting mitochondrial function via LOX-1. In summary, the L5-LOX-1 signaling axis plays an important role in cardiovascular aging and should be considered a new treatment target in this formidable disease.