Study of the association of mitochondrial and endoplasmic reticulum membranes in macrophages in the context of hypercholesterolemia: possible relevance for atherosclerosis

• Grant number: 17/03402-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: May 01, 2017
• End date: May 31, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Helena Coutinho Franco de Oliveira
• Grantee: Leandro Henrique de Paula Assis
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 17/17728-8 - Mitochondrial function and dysfunction: implications for aging and associated diseases, AP.TEM

Abstract

Atherosclerosis is the main cause of all cardiovascular diseases and related mortality. Elevated LDL-cholesterol in the plasma and local oxidative stress are early events in the atherogenesis process. Besides, macrophages recruited from the circulating blood monocytes and resident in the subendothelial space are key cells involved in the initiation and progression of atherosclerosis. Marked changes in the phenotype and function of macrophages occurs when they are exposed to inflammatory stimuli or oxidized LDL (oxLDL), including elevation of intracellular calcium and mitochondrial dysfunction. In this context, some structures named mitochondria associated membranes (MAM), transient sites of physical connection between mitochondria and endoplasmic reticulum (ER), may be related to calcium delivery to mitochondria in activated macrophages. In previous studies we demonstrated that hypercholesterolemic LDL receptor knockout mice (Ldlr -/-) present increased mitochondrial oxidative stress in several tissues compared with control animals. Thus, we hypothesized that cholesterol enriched macrophage membranes induces and/or stabilize MAM structures, increasing calcium ion flux to mitochondria, what is followed by organelle oxidative stress, membrane permeability transition and finally cell death. Consequently, these events may be relevant for the atherosclerosis progression. Therefore, in this work, we plan to develop a molecular tool to evaluate in vitro and in vivo whether MAM extension and stability in macrophages may be regulated by varying cholesterol concentrations as well as by drugs commonly used in the treatment of hypercholesterolemia. In addition, we plan to check whether MAM correlates with the severity of experimental atherosclerosis. (AU)

Scientific publications

(4)

(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)

ASSIS, LEANDRO HENRIQUE DE PAULA; DORIGHELLO, GABRIEL DE GABRIEL; DE OLIVEIRA, HELENA COUTINHO FRANCO. Pro-inflammatory polarization of macrophages is associated with reduced endoplasmic reticulum-mitochondria interaction. Biochemical and Biophysical Research Communications, v. 606, p. 7-pg., 2022-05-28. (13/50615-1, 17/17728-8, 17/02903-9, 17/03402-3)

DORIGHELLO, GABRIEL G.; ASSIS, LEANDRO H. P.; RENTZ, THIAGO; MORARI, JOSEANE; SANTANA, MONIQUE F. M.; PASSARELLI, MARISA; RIDGWAY, NEALE D.; VERCESI, ANIBAL E.; OLIVEIRA, HELENA C. F.. Novel Role of CETP in Macrophages: Reduction of Mitochondrial Oxidants Production and Modulation of Cell Immune-Metabolic Profile. ANTIOXIDANTS, v. 11, n. 9, p. 17-pg., 2022-09-01. (13/07607-8, 17/17728-8, 17/02903-9, 19/18431-4, 21/02401-9, 17/03402-3)

DORIGHELLO, GABRIEL G.; ROVANI, JULIANA C.; PAIM, BRUNO A.; RENTZ, THIAGO; ASSIS, LEANDRO H. P.; VERCESI, ANIBAL E.; OLIVEIRA, HELENA C. F.. Mild Mitochondrial Uncoupling Decreases Experimental Atherosclerosis, A Proof of Concept. JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS, v. 29, n. 6, p. 14-pg., 2022-01-01. (17/17728-8, 13/07607-8, 17/02903-9, 14/02819-0, 17/03402-3)

ASSIS, LEANDRO HENRIQUE DE PAULA; DORIGHELLO, GABRIEL DE GABRIEL; RENTZ, THIAGO; SOUZA, JANE CRISTINA DE; VERCESI, ANIBAL EUGENIO; DE OLIVEIRA, HELENA COUTINHO FRANCO. In Vivo Pravastatin Treatment Reverses Hypercholesterolemia Induced Mitochondria-Associated Membranes Contact Sites, Foam Cell Formation, and Phagocytosis in Macrophages. FRONTIERS IN MOLECULAR BIOSCIENCES, v. 9, p. 17-pg., 2022-03-15. (17/03402-3, 17/17728-8, 17/02903-9, 13/50615-1)