Elevated levels of total plasma homocysteine (Hcy), termed hyperhomocysteinemia (HHcy), are associated with increased incidence and mortality of chronic vascular diseases including coronary heart disease and stroke. However, the underlying biochemical mechanisms remain unknown. HHcy results in a significant elevation of intracellular levels of S- adenosylhomocysteine (SAH), a potent endogenous inhibitor of methyl-transfer reactions. Recently, we found that HHcy up-regulates the 5-Lipoxygenase (5- LO), an enzyme abundantly present in the vasculature, where it induces an increased formation of the amyloid beta peptide (Abeta) within the endothelial cells (EC). Once formed Abeta is rapidly eliminated along perivascular lymphatic drainage pathways. However, if the total amount of Abeta produced overcomes this ability, the peptide will accumulate in the arterial walls resulting in vascular inflammation and dysfunction. With time this condition will develop in amyloid angiopathy, which is characterized by excessive Abeta deposited also in the extracellular space of the artery wall, loss of smooth muscle cells and recruitment of circulating inflammatory cells. Taken together these data suggest a possible involvement of 5-LO in the HHcy-dependent vascular dysfunction and development of amyloid angiopathy, and support our central hypothesis: HHcy results in elevated intracellular SAH which by activating 5-LO induces an over- production of Abeta and its accumulation in the vasculature with subsequent vascular inflammation, endothelial dysfunction (ED) and ultimately amyloid angiopathy. To test our hypothesis we propose 3 linked specific Aims. In the first one, we will assess 5-LO activation and its contribution to vascular inflammation, ED and amyloid angiopathy in a mouse model of HHcy, the Tg-hCBS Cbs-/- mice. In the second one, we will determine the mechanisms by which HHcy induces 5-LO upregulation, and examine the role and mechanisms by which activated 5-LO regulates Abeta formation in EC. In the third one, we will establish the role of HHcy, and 5-LO upregulation in the development of the pathological vascular phenotype of the Tg-hCBS Cbs-/- mice.
Elevated levels of total plasma homocysteine (Hcy), termed hyperhomocysteinemia (HHcy), are associated with increased incidence and mortality of many human vascular diseases including coronary heart disease and stroke. However, the underlying mechanisms responsible for this increase remain unknown. Among other things, HHcy elevates the activity of a protein enzyme in the vasculature called 5-Lipoxygenase (5-LO). Once this protein is activated, it induces the formation and accumulation of the amyloid beta peptide inside the endothelial cells of the arterial wall. With time this accumulation translates in an altered response of the vasculature to normal stimuli and at the same time an intense vascular inflammation. This condition will ultimately result in a permanent damage to the artery with possible reduction of blood flow or lesion of the wall and hemorrhage/bleeding. In the proposed studies we want to demonstrate that the 5-LO is responsible for the vascular damage deriving from a condition of HHcy. If we prove this hypothesis, our findings will provide important information for future human studies with specific drug inhibitors of 5-LO as a novel therapy for the treatment of chronic vascular diseases secondary to HHcy.
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