Modulation of vascular calcification by protein disulfide isomerase: study on a new transgenic mouse model

• Grant number: 15/25923-0
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): March 01, 2016
• Effective date (End): June 30, 2018
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Francisco Rafael Martins Laurindo
• Grantee: Luciana Pescatore Alves
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated research grant: 13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID

Abstract

Vascular calcification is an active pathophysiological process related to trophic and inflammatory phenomena, which reduces vascular compliance and is associated with higher morbidity and mortality. However, mechanisms promoting vascular calcification are still poorly understood, which impacts in the absence of effective medical therapies. Oxidative stress and endoplasmic reticulum (ER) stress have been implicated in cardiovascular calcification progression. Those pathways converge into ER-protein mediated signaling by protein disulfide isomerases, among which PDI A1 (PDI) is the prototype. Previous work suggests that PDI overexpression enhances Nox1 NADPH oxidase activation, while at the same time it can protect against ER stress. In this context, in vivo studies using PDI overexpressing mice may reveal important vascular calcification mechanisms. Our group recently developed and validated a new PDI overexpression mice model. Our hypothesis is that PDI transgenic (TgPDI) mice are protected against vascular calcification. Possible mechanisms involved in this effect may involve optimized protein folding in the ER, among others. The aim of our project is to evaluate the role of PDI in in vivo and in vitro models (of smooth muscle cells, VSMC) of vascular calcification using the TgPDI mouse. The specific aims are: I) to measure and compare the intensity of aortic vascular calcification in two different models: a) in vivo, using TgPDI or wild-type mice; b) in vitro, using cultured VSMC from aortic TgPDI and wild-type (WT) mice after calcifying stimulus with beta-glycerophosphate / Vitamin-D3 / CaCl2 or BMP-2. II) to evaluate the osteocondrogenic dedifferentiation of VSMC by analyzing osteocondrogenic mRNA and proteins expression (RUNX2, MSX2, alkaline phosphatase and beta-catenin), in the same experimental models described in aim (I) . III) To investigate functional relevance of ER stress, with regard to its interaction with PDI and VSMC osteocondrogenic dedifferentiation signaling, and finally to vascular calcification progression (in the same experimental models described in aim I). Preliminary results suggest less calcification in TgPDI mouse. These results may contribute to improved mechanistic understanding and identification of possible therapeutic targets of vascualr calcification.

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)

CARMO, LUCIANA S.; BURDMANN, EMMANUEL A.; FESSEL, MELISSA R.; ALMEIDA, YOURI E.; PESCATORE, LUCIANA A.; FARIAS-SILVA, ELISANGELA; GAMARRA, LIONEL F.; LOPES, GABRIEL H.; ALOIA, THIAGO P. A.; LIBERMAN, MARCEL. Expansive Vascular Remodeling and Increased Vascular Calcification Response to Cholecalciferol in a Murine Model of Obesity and Insulin Resistance. ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, v. 39, n. 2, p. 200-211, FEB 2019. (13/09652-0, 13/09611-2, 15/25923-0)

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; et al. 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. (13/09652-0, 16/17961-1, 13/09611-2, 15/25923-0)

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. (15/25923-0, 16/17961-1, 16/21470-3)