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Role of gamma-carboxyglutamic protein functional imbalance in vascular calcification modulation of diabetic patients with peripheral arterial disease


Obstructive atherosclerotic lesions of vessels distal to aortic bifurcation (iliac artery), decreasing oxygen delivery to tissues is the hallmark of obstructive peripheral arterial disease (PAD). The most important complication of PAD is extremity amputation, in which peripheral arterial insufficiency (ischemia) participates of its pathophysiology in 80% of cases. Amputations due to PAD occur predominantly in lower-extremities (85%). PAD has high incidence in patients with diabetes mellitus (DM), that also constitutes in a risk factor for heart failure and coronary artery disease. To depict the importance of diabetes, 45% of patients submitted to lower-limb amputation (LLA) caused by PAD have DM.In diabetic and PAD patients, vascular calcification (VC) coincidently is very prevalent. VC implicates in higher risk of obstruction of blood flow, through effects that worsen vascular blood flow auto-regulation, such as increase in vascular rigidity and pulse pressure (Windkessel effect), thus contributing to limb claudication progression and limb infection (diabetic foot), finally causing lower limb amputation. Previously considered a passive degenerative disease of aging, VC is now understood as a pathophysiologic condition mediated by specific cellular signaling and stimulatory/inhibitory mediators. Although studies pointed out an association between VC and DAP in patients with DM, signaling mechanisms that promote or attenuate VC progression in DM are scarce. To understand this specific pathophysiology and cellular signaling we studied VC in animal model of DM, specifically in obesity and insulin resistance (ob/ob mice). We described that BMP-2 (bone morphogenetic protein-2), an osteogenic stimulus, present in coronary plaques and in PAD, promotes increased ob/ob vascular smooth muscle cells (VSMCs) osteoblastic dedifferentiation in comparison to C57BL/6, by increasing MSX2 and RUNX2 and finally increasing VSMCs calcification.Conversely, MGP (gamma-carboxyglutamic protein) has important inhibitory role in VC progression. Its active form occurs by post-translational modification dependent on Vitamin K, which promotes carboxylation of glutamic residues, besides being phosphorylated in serine residues. MGP knockout mice develop calcification through the entire vascular wall, determining higher mortality. Clinical studies in patients with renal failure and DM demonstrated increased serum dephosphorylated MGP, in uncarboxylated form (inactive form) coincidently in individuals with higher prevalence of VC. Although they found this biomarker, its functional role in cellular signaling to determine VSMC dedifferentiation into osteochondrogenic cells is unknown. This scenario motivated us to conceive this proposal, conceptually focused on a translational design study, by isolating VSMCs from amputated arterial segments in order to quantify specific genomic and proteomic profile through a calcifying model in culture and assessing inhibitory role of MGP active/inactive forms. This model can unveil relevant aspects of the role of MGP in specific modulation of cellular signaling pathways during VSMCs osteogenic differentiation, more importantly in diabetic amputated patients. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
ALMEIDA, YOURI E.; FESSEL, MELISSA R.; DO CARMO, LUCIANA SIMAO; JORGETTI, VANDA; FARIAS-SILVA, ELISANGELA; PESCATORE, LUCIANA ALVES; GAMARRA, LIONEL F.; ANDRADE, MARIA CLAUDINA; SIMPLICIO-FILHO, ANTONIO; PITANGUEIRAS MANGUEIRA, CRISTOVAO LUIS; RANGEL, ERIKA B.; LIBERMAN, MARCEL. Excessive cholecalciferol supplementation increases kidney dysfunction associated with intrarenal artery calcification in obese insulin-resistant mice. SCIENTIFIC REPORTS, v. 10, n. 1 JAN 9 2020. Web of Science Citations: 0.
PESCATORE, LUCIANA A.; GAMARRA, LIONEL F.; LIBERMAN, MARCEL. Multifaceted Mechanisms of Vascular Calcification in Aging. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, v. 39, n. 7, p. 1307-1316, JUL 2019. Web of Science Citations: 1.

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