Effect of the association between arterial hypertension and Walker-256 cancer on the cardiac phenotype and tumor progression: therapeutic potential of aerobic exercise training

• Grant number: 21/06229-6
• Support type: Scholarships in Brazil - Master
• Effective date (Start): May 01, 2022
• Effective date (End): July 31, 2023
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal researcher: Tiago Fernandes
• Grantee: Luis Felipe Rodrigues
• Home Institution: Escola de Educação Física e Esporte (EEFE). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cardiovascular diseases (CVD), followed by cancers, are the leading causes of death worldwide; recognized for being complex diseases with a multifactorial cause, and that they have a common interaction and risk factors. In recent decades, cardio-oncology has focused on the prevention and treatment of CVD in cancer survivors as a result of the cardiotoxicity of antineoplastic agents. On the other hand, there is a growing body of epidemiological evidence demonstrating that CVD is a pro-oncogenic factor since patients with CVD have a higher incidence of cancer compared to healthy groups. An association between high blood pressure (AH) and cancer incidence/mortality in humans has been implemented. It is possible that the bidirectional relationship of diseases can potentiate cardiac damage, however little is known about their association and the mechanisms related to this phenomenon. Aerobic exercise training (AET) has been used as an important non-pharmacological therapy to relieve symptoms, improve exercise tolerance, improve quality of life, and reduce hospitalization of patients with CVD and cancer. However, the effects of AET on cardiac repercussions in the association of CVD with cancer are unknown. Thus, the present study aims to investigate an association between AH and cancer in cardiac phenotypic changes and tumor progression in rats and verify the therapeutic role of AET on cardiomyopathy and a functional disability induced by the bidirectional relationship between the diseases. Both the spontaneously hypertensive animal (SHR) model of AH and the Walker-256 tumor cancer model were selected due to the similarity of their physiopathogenesis in humans. 50 Wistar Kyoto rats and 50 SHR will be used. Implantation of the Walker-256 carcinoma will be performed in the subcutaneous tissue of the right flank region. The animals will be trained for 6 weeks, 60 min sessions, once a day, 5 times a week, with a gradual increase in workload. Will be evaluated: blood pressure and heart rate at rest, tolerance to maximum physical effort, ventricular function and structure, tumor growth, cardiac and skeletal muscle mass, percentage of cachexia, and citrate synthase enzyme activity. It will also be measured the diameter of cardiomyocytes, cardiac fibrosis, and capillary to cardiac fiber ratio by the histological method. Expression of genes for pathological cardiac hypertrophy and collagen content, miRNA-208 family, and protein expression analysis for cell survival and apoptosis pathways. Statistical analyzes will be performed by the program's Statistica software. After standardizing the culture of tumor cells and the cancer cachexia model in the experimental models proposed in the study, the preliminary results obtained suggest that AH induces a greater tumor development and a highest level of cachexia when associated with cancer, indicating the viability of the project. (AU)