Experimental periodontitis in genetically modified mice (VAChT and Super VAChT): cardiovascular and inflammatory aspects

• Grant number: 22/07579-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: February 01, 2023
• Status: Discontinued
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Helio Cesar Salgado
• Grantee: Thaís Marques da Silva
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 20/06043-7 - Autonomic (sympathetic and parasympathetic) modulation of cardiovascular and inflammatory responses under physiopathological clinical and experimental conditions, AP.TEM
• Associated scholarship(s): 23/18278-7 - Non-invasive neuromodulation in bipolar depression to improve symptoms and reduce low-grade chronic inflammation and cardiovascular risk., BE.EP.PD

Abstract

Prado et al. (2006) developed a strain of genetically modified mice, which show attenuation of the vesicular acetylcholine transporter (VAChT) (Prado et al., 2006). This strain was named VAChT knockdown (VAChT KD). It is known that even a modest deficiency of VAChT is enough to interfere with neurotransmitter release, thus attenuating Parasympathetic Function. On the other hand, Zhao et al. (2011) developed another genetically modified mouse model, opposite to the one previously mentioned (VAChT KD), however, with overexpression of cholinergic neurotransmission, which was called Super VAChT mouse (Zhao et al., 2011). In these animals, there is normally a threefold increase in ACh release. It is understood, therefore, that the Super VAChT mouse model is essential to examine whether the increase in VAChT expression, as opposed to the VAChT KD model, thus evidencing a beneficial role in the exacerbation of Parasympathetic Function, especially during the development of periodontitis induced by Porphyromonas gingivalis. Objective. To examine the role of the Parasympathetic Autonomic Nervous System in cardiocirculatory (blood pressure, heart rate variability, cardiac function, and remodeling) and inflammatory (bone loss and cytokines) responses in the Porphyromonas gingivalis-induced periodontitis model.Scientific and Technological Challenges: The first challenge of this study is to verify if the impairment of Parasympathetic Function in VAChT KD animals would have an undesirable effect, exacerbating inflammatory responses (bone loss and cytokines), and compromising cardiocirculatory responses (blood pressure, heart rate variability, cardiac function, and remodeling) in the model of Periodontitis induced by Porphyromonas gingivalis. The second challenge is to verify whether the enhancement of Parasympathetic Function in Super VAChT animals would play a "protective" role against the harmful effects of Periodontitis induced by Porphyromonas gingivalis, particularly concerning the cardiocirculatory and inflammatory changes highlighted above.Means and Methods: Subject VAChT KD and Super VAChT animals to Periodontitis induced by Porphyromonas gingivalis and perform the following approaches: 1. Hemodynamic study [blood pressure, heart rate, and variability of blood pressure and heart rate (HRV)] and function baroreflex through Telemetry records of blood pressure and heart rate; 2) Study of cardiac function through echocardiography and recording of left ventricular pressure with the Millar catheter; 3) Study of cardiac remodeling through echocardiography, histology, and morphology; 4) Study of bone loss through histological analysis with hematoxylin-eosin, photomicrography of the sagittal section of the molars, and 3D computed microtomography; 5) Study of inflammatory responses by measuring inflammatory cytokines [TNF-±, IL-6, IL-10 and interferon (IFN)-³], and anti-inflammatory (IL-10); 6) Study of the function of the Sympathetic Autonomic Nervous System using plasma noradrenaline dosage. Expected results. To characterize the performance of the Parasympathetic Autonomic Nervous System, through its attenuation, as well as through its over-expression in the following responses: 1) hemodynamic [blood pressure, heart rate, and blood pressure and heart rate (HRV) variability ]; 2) baroreflex function; cardiac function (cardiac output, ejection fraction, shortening fraction, through echocardiography and left ventricular cannulation with the Millar catheter); 3) cardiac remodeling (histopathological analysis of myocyte size and fibrosis); 4) inflammatory responses (bone loss and cytokines), in the model of periodontitis induced by Porphyromonas gingivalis. (AU)