Analysis of myocardial remodeling in mice exposed to air pollution during and after their pregnancy

• Grant number: 18/01305-3
• Support type: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): April 01, 2018
• Effective date (End): March 31, 2019
• Field of knowledge: Health Sciences - Medicine
• Principal researcher: Paulo Hilário Nascimento Saldiva
• Grantee: Adriana Morgan de Oliveira Fonoff
• Supervisor abroad: Loren e Wold
• Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Ohio State University, Columbus, United States
• Associated to the scholarship: 15/04103-4 - Analysis of myocardial remodeling in mice exposed to air pollution during and after their pregnancy, BP.PD

Abstract

Cardiovascular disease (CVD) is the leading global cause of death and accounts for 17.3 million deaths per year and is expected to grow to greater than 23.6 million by 2030 [1]. Heart failure and ischemic heart disease are the main causes of cardiovascular deaths. Growing evidence supports a strong and likely causal association between CVD, and its risk factors, with incidence of cognitive decline and Alzheimer's disease (AD). Individuals with subclinical CVD are at higher risk for developing AD. Previous studies demonstrate a link to heart failure (HF) as a risk factor for Alzheimer's disease (AD). Compromise blood flow to the brain is a major determinant for the "heart-to-head" connection. The inability of the heart to maintain adequate blood flow to the active regions of the brain constitutes the primary pathogenic contributor to AD. It has been shown earlier that cognitive decline from impaired blood flow to the brain in pre-symptomatic AD, while increasing blood flow to the brain improves AD symptoms. Because the brain is a highly metabolically active organ that receives about 20% of cardiac output, it is vulnerable to hypoxia induced by reduced blood flow due to atherosclerosis and/or HF. Reports suggested that accumulation of Amyloid Precursor Protein (APP) aggregates serve as a biochemical marker that defines the degree of pathogenicity of AD. There is considerable evidence that links effect of air pollution to cardiovascular mortality and morbidity and with poorer cognitive function in the aging population. It has been shown that 6 months exposure to air pollution reported to cause neuroinflammation and elevated early markers of neurodegenerative disease. The exposure to PM2.5 from ambient air pollution on older women without dementia showed reduction of brain volumes especially the white matter. Another study showed an early brain imbalance in oxidative stress, inflammation, innate and adaptive immune response-associated genes, and BBB breakdown from exposures of urban air pollution. In the brain, air pollution has been shown to correlate with atrophy of total cerebral volume in older adults living in the New England and New York areas. On the other hand, air pollution is known to worsen atherosclerotic burden in the carotid arteries and to have among the strongest adverse cardiovascular health effects. Recent scientific evidence signals a more complex, interdependent link and progression of the two diseases. However, there is still no scientific evidence on the pathological link between the two diseases. The current proposal will conduct a thorough investigation of the pathogenic link between HF and AD in the context of exposure to particulate matter (air pollution). In the present proposal, we aim to study the effect of air pollution on cognitive and cardiac functions. We hypothesize that air particulate matter accelerate the pathological accumulation of protein aggregates thus causing cardiac and cognitive dysfunction. Aim 1: To study the adverse effects of PM2.5 on cardio and neurological functions in AD prone mice and Aim 2: To identify the molecular mechanisms by which exposure to PM2.5 impair cardiac and cognitive function in AD prone mice. Expected results: we anticipate the increase in ROS production (determined by a series of biochemical and molecular assays) following PM2.5 exposure in heart and brain of AD prone mice. We also anticipate altered redox state and a lower GSH/GSSG ratio and an altered reduced/oxidized ratio of both Trx1 and Trx2, reflecting deficient ROS buffering capacity from these enzymes, in hearts, myocytes and neurons of AD prone PM2.5-exposed mice. (AU)