• Responsabile: dott.ssa Vittoria Arcidiacono

Background and Significance
Cardiovascular disease (CVD) is the leading cause of death worldwide and in chronic kidney disease (CKD) patients the risk of mortality from CVD is 15 times over that in the general population. Vitamin D (VD) deficiency (serum 25(OH)vitaminD<15ng/ml) is a newly recognized risk factor for CV lesions in health and a predictor of CV mortality in the CKD population. Indeed, not only it increases vascular calcification through the elevation of serum PTH and PTH-driven mineral/skeletal abnormalities, causing ectopic calcium deposition, but more significantly, it is associated to atheromatous disease. During the atheromatous process, the increase in adventitial vasa vasorum (VV) promotes endothelial dysfunction
(early stages) and plaque instability (advances stages). Importantly, the active form of VD, besides suppressing secondary hyperparathyroidism in CKD patients, was reported to suppress neoangiogenesis, endothelial cells proliferation and to counteract the increase/activation of metalloproteinase TACE (TNFa converting enzyme). In this context, by using a murine model of atheromatosis (ApoE-/- mice), the main goal of this proposal is to delineate the cause/effect link between systemic VD status, TACE activation, neovascularization, arterial wall thickening, plaque formation and instability in both health and kidney disease. These studies will contribute to identify key therapeutic targets and optimal VD status to prevent the onset and the progression of atheromatous disease.
Specific aims
Aim 1: To comparatively analyze the time course for the onset and progression of atheromatosis in ApoE-/- mice characterized by (a) normal or (b) deficient VD levels. Specifically, we will examine the association between markers of systemic inflammation, secondary hyperparathyroidism, classical risk factors for atheromatosis and VD status with the increase in adventitial/intraplaque VV and plaque formation/composition.
Aim 2: To determine the effect of VD deficiency on the onset and progression of atheromatous disease in a murine model of CKD. To this end, we will assess the association between markers of renal dysfunction, systemic inflammation, secondary hyperparathyroidism, classical risk factors for atheromatosis and VD status with the increases in adventitial/intraplaque VV, plaque formation/composition.
Aim 3: To identify the optimal VD intervention able to prevent/delay the onset and/or progression of atheromatous disease. For this purpose, by using the ApoE-/- mouse models, we will assess the efficacy of supplementation with (a) nutritional VD3 (cholecalciferol) or (b) nutritional plus active VD treatment.
Vitamin D deficiency, both in the population with normal kidney function or in patients with CKD, promotes the increases of the arterial adventitial vasa vasorum, as well as systemic inflammation, inflammatory vascular infiltration and foam cell formation that lead to plaque formation and instability. Therefore, correction of vitamin D deficiency in health and nutritional/active VD in CKD could prevent the onset or slow the progression of atheromatous disease.
Impact and Translational Implications
The full delineation of the cause/effect link between systemic vitamin D status and the onset of subclinical atheromatosis, and/or its progression to cause death, is essential to support the therapeutic use of VD interventions for the general population and for chronic kidney disease patients in order to prevent CVD. Moreover, the results deriving from this project will allow the identification of the most sensitive early markers to monitor the efficacy of personalized VD interventions.


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