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Impact of insulin resistance on the progression of vascular calcification

Abstract

Vascular and degenerative aortic valve calcification is important pathophysiological processes, associated with coronary artery disease, implicating in greater morbidity and mortality. It is also very prevalent in patients with other cardiovascular risk factors such as chronic renal disease, diabetes mellitus, hypercholesterolemia and aging. Previously defined as a passive degenerative disease, vascular/valve calcification is now considered a very complex mediated process with activators and inhibitors, which can increase ectopic mineralization (inflammation, oxidative stress, oxidized-LDL, bone morphogenic proteins (BMPs), TGF-², apoptosis, increased Ca++ x P product and elevated Vitamin D3) or inhibit it (MGP, Fetuin A, pyrophosphate, and osteopontin) respectively. Although some pertinent mechanisms were already described, such studies were performed using increased Ca++ x P and Vitamina D3 which specifically does not resemble important aspects of human disease. Recently, during my post-doctoral fellowship we developed another vascular smooth muscle cell calcification model using BMP2. Diabetes mellitus and insulin resistance are prevalent conditions in the Western World and can incur devastating complications with high mortality. As mentioned, vascular calcification is also increased in this population. However, the coincidence of multiple risk factors in patients with diabetes/insulin resistance complicates the understanding of the mechanisms of vascular calcification specifically due to diabetes/insulin resistance. The main hypothesis of this investigation is that insulin resistance can initiate important signaling cascades that stimulate ectopic mineralization and vascular smooth muscle cell transition into an osteochondrogenic phenotype in vitro and in vivo. Therefore, the main proposal of this study is to investigate if vascular smooth muscle cells under insulin resistance have increased mineralization after a calcifying stimulus such as BMP2 in comparison with cells under normal conditions and to evaluate if insulin resistance potentiates vascular calcification in vivo. The objectives of this project are: a) to further investigate this model of vascular smooth muscle cell calcification in vitro e in vivo developed during my post-doctoral fellowship, that could demonstrate important vascular calcification signaling mechanisms, that resembles human disease; b) to analyze the mechanisms by which insulin resistance could potentiate vascular calcification. These experiments can clarify potential targets for future therapeutic strategies that could abrogate or prevent the development of vascular calcification and its complications, especially under insulin resistance. (AU)

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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)
ANDRADE, MARIA CLAUDINA; CARMO, LUCIANA S.; FARIAS-SILVA, ELISANGELA; LIBERMAN, MARCEL. Msx2 is required for vascular smooth muscle cells osteoblastic differentiation but not calcification in insulin-resistant ob/ob mice. ATHEROSCLEROSIS, v. 265, p. 14-21, OCT 2017. Web of Science Citations: 5.
HILAIRE, CYNTHIA ST; LIBERMAN, MARCEL; MILLER, JORDAN D.; COMM, EARLY CAREER. Bidirectional Translation in Cardiovascular Calcification. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, v. 36, n. 3, p. E19-E24, MAR 2016. Web of Science Citations: 4.

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