1.
Vitamin D Effects on Bone Homeostasis and Cardiovascular System in Patients with Chronic Kidney Disease and Renal Transplant Recipients.
Cianciolo, G, Cappuccilli, M, Tondolo, F, Gasperoni, L, Zappulo, F, Barbuto, S, Iacovella, F, Conte, D, Capelli, I, La Manna, G
Nutrients. 2021;(5)
Abstract
Poor vitamin D status is common in patients with impaired renal function and represents one main component of the complex scenario of chronic kidney disease-mineral and bone disorder (CKD-MBD). Therapeutic and dietary efforts to limit the consequences of uremia-associated vitamin D deficiency are a current hot topic for researchers and clinicians in the nephrology area. Evidence indicates that the low levels of vitamin D in patients with CKD stage above 4 (GFR < 15 mL/min) have a multifactorial origin, mainly related to uremic malnutrition, namely impaired gastrointestinal absorption, dietary restrictions (low-protein and low-phosphate diets), and proteinuria. This condition is further worsened by the compromised response of CKD patients to high-dose cholecalciferol supplementation due to the defective activation of renal hydroxylation of vitamin D. Currently, the literature lacks large and interventional studies on the so-called non-calcemic activities of vitamin D and, above all, the modulation of renal and cardiovascular functions and immune response. Here, we review the current state of the art of the benefits of supplementation with native vitamin D in various clinical settings of nephrological interest: CKD, dialysis, and renal transplant, with a special focus on the effects on bone homeostasis and cardiovascular outcomes.
2.
Assessing statin effects on cardiovascular pathways in HIV using a novel proteomics approach: Analysis of data from INTREPID, a randomized controlled trial.
Toribio, M, Fitch, KV, Stone, L, Zanni, MV, Lo, J, de Filippi, C, Sponseller, CA, Lee, H, Grundberg, I, Thompson, MA, et al
EBioMedicine. 2018;:58-66
Abstract
BACKGROUND People with HIV (PWH) demonstrate increased cardiovascular disease (CVD), due in part to increased immune activation, inflammation, and endothelial dysfunction. METHODS In a randomized trial (INTREPID), 252 HIV-infected participants with dyslipidemia and no history of coronary artery disease were randomized (1:1) to pitavastatin 4 mg vs. pravastatin 40 mg for 52 weeks. Using a proteomic discovery approach, 92 proteins biomarkers were assessed using Proximity Extension Assay technology to determine the effects of statins on key atherosclerosis and CVD pathways among PWH. 225 participants had specimens available for biomarker analysis pre- and post-baseline. FINDINGS The mean age was 49.5 ± 8.0 (mean ± SD), LDL-C 155 ± 25 mg/dl and CD4 count 620 ± 243 cell/mm3. Among all participants, three proteins significantly decreased: tissue factor pathway inhibitor [TFPI; t-statistic = -6.38, FDR p-value<0.0001], paraoxonase 3 [PON3; t-statistic = -4.64, FDR p-value = 0.0003], and LDL-receptor [LDLR; t-statistic = -4.45, FDR p-value = 0.0004]; and two proteins significantly increased galectin-4 [Gal-4; t-statistic = 3.50, FDR p-value = 0.01] and insulin-like growth factor binding protein 2 [IGFBP-2; t-statistic = 3.21, FDR p-value = 0.03]. The change in TFPI was significantly different between the pitavastatin and pravastatin groups. Among all participants, change in TFPI related to the change in LDL-C (r = 0.43, P < 0.0001) and change in Lp-PLA2 (r = 0.29, P < 0.0001). INTERPRETATION Using a proteomics approach, we demonstrated that statins led to a significant reduction in the levels of TFPI, PON3, and LDLR and an increase in Gal-4 and IGFBP-2, key proteins involved in coagulation, redox signaling, oxidative stress, and glucose metabolism. Pitavastatin led to a greater reduction in TFPI than pravastatin. These data highlight potential novel mechanisms of statin effects among PWH. FUND This work was supported by an investigator-initiated grant to S.K.G. from KOWA Pharmaceuticals America, Inc. and the National Institutes of Health [P30 DK040561; Nutrition Obesity Research Center at Harvard]. M.T. was support by National Institutes of Health [5KL2TR001100-05; Harvard Catalyst KL2 grant].
3.
Anthrax toxin: pathologic effects on the cardiovascular system.
Golden, HB, Watson, LE, Lal, H, Verma, SK, Foster, DM, Kuo, SR, Sharma, A, Frankel, A, Dostal, DE
Frontiers in bioscience (Landmark edition). 2009;(6):2335-57
Abstract
Anthrax is a disease caused by infection with spores from the bacteria Bacillus anthracis. After entering the body, the spores germinate into bacteria and secrete a toxin that causes local edema and, in systemic infections, cardiovascular collapse and death. The toxin is a tripartite polypeptide, consisting of protective antigen (PA), lethal factor (LF) and edema factor (EF), which have key roles in the bacterial pathogenesis and disease progression. PA facilitates transfer of LF and EF to the cytosol. Lethal toxin is a zinc metalloproteinase, which has the capacity to inactivate mitogen-activated protein (MAP) kinase kinase (MEK) and stimulates the release of sepsis-related cytokines tumor necrosis factor-alpha and interleukin-1beta. Edema factor is a calmodulin (CaM)-dependent adenylate cyclase, which increases levels of cyclic AMP, causing impaired neutrophil function and disruption of water balance that ultimately results in massive tissue edema. Together, the toxins effectively inhibit host innate and adaptive immune responses, allowing the bacteria to grow unrestrained and overwhelming any resistance. Clinically, inhalational anthrax presents in a biphasic pattern with initial nonspecific "flu-like" symptoms nausea and vomiting 1 to 4 days after exposure, followed by severe illness with dyspnea, high fever and circulatory shock. The latter symptoms represent a terminal stage and treatment is often ineffective when started at that time. Key indicators of early anthrax cardiovascular-related pathogenesis include mediastinal widening in association with pleural effusion and edema. In this review, we describe the current understanding of anthrax toxins on cellular function in the context of cardiovascular function and discuss potential therapeutic strategies.