Laboratório de Fisiologia Cardiovascular

REDOX SIGNALING IN THE PROGRESSION OF HEART HYPERTROPHY TO RIGHT HEART FAILURE VIA ASK-1/JNK/Bcl-2/CASPASE-9/CASPASE-3
 
Description: Studies have shown that the GSH/GSSG redox imbalance and the increase in intracellular hydrogen peroxide concentration, resulting from right heart failure by the monocrotaline model, activates the JNK pathway via ASK-1, increasing the synthesis of caspase-3 by the inhibition of bcl-2. This converges to activation of apoptotic signaling in the transition process from compensatory cardiac hypertrophy to right ventricular failure, leading to structural modification of cardiomyocytes and consequent change in cardiac mechanics. Therefore, this project aims to evaluate the oxidative stress of the right ventricle through measures of oxidative damage and glutathione metabolism, relating it to the morphometric evaluation and the expression of proteins of the MAPK family (JNK) in rats submitted to right heart failure due to pulmonary hypertension.
 
THE INFLUENCE OF AEROBIC PHYSICAL EXERCISE ON CARDIAC AND PULMONARY VASCULAR REMODELING IN COR PULMONALE MODEL
 
Description: The role of physical exercise on adverse right ventricular remodeling induced by monocrotaline-induced pulmonary arterial hypertension. Relevance of the redox state on the signaling pathways involved in survival and cell death linked to this experimental model.
 
EFFECT OF THYROID HORMONES ON REDOX STATUS AND POST-INFARCTION REMODELING
 
Description: Acute myocardial infarction is an ischemic heart disease and leads to an adaptive hypertrophic response of the heart tissue, which progresses to heart failure. Many studies demonstrate the involvement of reactive oxygen species in this progression, through the regulation of signaling pathways sensitive to the redox state. In this context, studies have shown a cardioprotective role of thyroid hormones in maintaining post-infarction cardiac function. The objective of this project is, therefore, to evaluate the role of reactive oxygen species on the effects of thyroid hormones on post-infarction cardiac remodeling and on the activation of signaling pathways involved with cell survival and apoptosis sensitive to the redox state in the heart tissue. Male Wistar rats will be used, divided into four groups: Group Infarction (AMI), Group Infarction + treatment with thyroid hormones (AMI + TH), Group SHAM (SHAM) and Group SHAM + treatment with thyroid hormones thyroid (SHAM + HT). The AMI and AMI + HT groups will undergo infarction through the anterior descending coronary artery ligation technique, while the other groups will undergo all surgical procedures, with the exception of artery ligation. After that, the animals in the AMI + HT and SHAM + HT groups will receive hormonal treatment with 6 μg/day of T3 and 24 μg/day of T4 in aqueous solution for 28 days, the other two groups only in aqueous solution. After hormone treatment, the evaluation of hemodynamic parameters will be performed through left ventricular catheterization. Then, the animals will be euthanized and blood will be collected for measurement of serum T3, T4 and TSH levels. Cardiac tissue will also be collected for assessment of oxidative stress and some signaling proteins sensitive to the redox state (total AKT, phosphorylated AKT, total ERK1/2, phosphorylated ERK1/2, JNK.
 
 
INFLUENCE OF THE REDOX STATE ON THE MODULATION OF CALCIUM MANAGEMENT PROTEINS AND THE DEVELOPMENT OF CARDIAC HYPERTROPHY INDUCED BY HYPERTHYROIDISM
 
Description: The high concentration of thyroid hormones has a considerable influence on the cardiovascular system, being indicated as a risk factor in the development of heart failure. Increased oxygen consumption, a characteristic condition of hyperthyroidism, can lead to the formation of active oxygen species (AOS). AOS play an important role in cardiac cell signaling, acting as messengers that can propagate apoptotic or hypertrophic stimuli, depending on their concentrations. Allied to this, the establishment of cardiac hypertrophy in response to hyperthyroidism has also been related to the altered activity of calcium management proteins, affecting the contractile capacity of cardiac tissue. Thus, it is important to understand the molecular mechanisms involved in intracellular signaling, mediated by AOS in cardiac alterations evidenced in hyperthyroidism.
 
EFFECT OF VITAMIN C ON REDOX SIGNALING FOR CARDIAC REMODELING INDUCED BY HYPERTHYROIDISM AND MEDIATED BY THE RENIN-ANGIOTENSIN SYSTEM
 
Description: Hyperthyroidism represents one of the most relevant endocrine alterations (according to the Brazilian Society of Endocrinology and Metabolism). Cardiac hypertrophy, caused by excess thyroid hormones, is considered a risk factor for morbidity and mortality, for the development of dilated cardiomyopathy and heart failure in hyperthyroidism. One of the factors related to these cardiac dysfunctions is activation of the renin angiotensin system (RAS) in hyperthyroid patients. It is described that the Ang II-AT1 complex, formed in the cell membrane, triggers intracellular signaling, resulting in increased protein synthesis and consequent hypertrophy. In parallel, the Ang II-AT1 complex is also involved in the production of active oxygen species (AOS). Recently, new concepts redefine the role of AOS, considering them as molecules responsible for intracellular signaling processes for cell growth and death, as well as for the development of cardiac hypertrophy induced by hyperthyroidism. On the other hand, in hyperthyroidism, an increase in the expression of the isoforms of the enzyme nitric oxide synthase (NOS) has also been reported, with a consequent increase in the production of nitric oxide (NO). NO plays an important role not only as a vasodilator, but also as an antihypertrophic agent. Thus, the high levels of NO observed in hyperthyroidism could represent a counter-regulatory response to the development of hypertrophy and progression to heart failure.
 
EFFECTS OF SULFORAPHANE ON INFLAMMATORY PARAMETERS AND OXIDATIVE STRESS IN AN ISCHEMIA-REPERFUSION MODEL IN ISOLATED RAT HEART
 
Description: Cardiovascular diseases such as coronary artery disease are responsible for high rates of mortality and morbidity, in addition to high costs. Oxidative stress is related to the pathogenesis of these diseases, including ischemic disease, through increased generation of reactive oxygen species and decreased antioxidant defenses. Several studies have invested in the search for exogenous antioxidants that can minimize the damage caused by these species in cardiovascular diseases. However, these antioxidants may have a beneficial role only at the beginning of the treatment, therefore, it is necessary to search for alternative compounds to them. One of the compounds that acts by increasing the antioxidant reserve is Sulforaphane, found in vegetables such as broccoli, a food that is easily accessible to the population. Sulforaphane activates the Nrf-2 pathway, a transcription factor that promotes the expression of endogenous antioxidants, as well as a decrease in the pro-inflammatory response. Since this compound has the aforementioned properties, the objective of this study is to evaluate the prophylactic role of sulforaphane in oxidative stress and in inflammatory parameters in the heart of rats submitted to ischemia-reperfusion.
 
 
EFFECTS OF SULFORAPHAN ON RIGHT VENTRICLE REMODELING AND REDOX STATE IN A MODEL OF PULMONARY ARTERIAL HYPERTENSION
 
Description: Pulmonary arterial hypertension (PAH) is a serious and fatal disease, clinically characterized by increased pulmonary vascular resistance, which affects the heart. This disease affects more women than men, in a ratio of 2:1, and can manifest at any age, being more common around 37 years old. The prevalence of PAH is generally low. In a study conducted in France, the estimated prevalence was 15 cases/million adults, and the incidence was 2.4 cases/million inhabitants/year. One-year survival was 88% in this study, however, the diagnosis of PAH is usually performed in advanced stages of the disease, when most patients already exhibit severe functional and hemodynamic impairment, leading to a poor prognosis. It is believed that regardless of the initiation process, there is an imbalance in the secretion of vasoactive factors, leading to an excess of vasoconstriction that stimulates vascular remodeling through pathological cellular processes. Studies in animal models suggest the participation of reactive oxygen species and oxidative stress in this process, as well as in hypertrophy and contractile dysfunction of the right ventricle (RV). Heme oxygenase (HO)-1 is an oxidative stress-responsive enzyme that has cardioprotective and anti-inflammatory properties. Recently, in a model of PAH induction by chronic systemic-pulmonary shunt, it was shown that PAH and RV failure are associated with the downregulation of HO-1 signaling and the activation of local inflammatory processes. Considering that, we propose a study focusing on the role of sulforane (isothiocyanate abundant in broccoli) in the activation of antioxidant defenses through the activation of Nrf2. Therefore, this can be a complementary treatment in this disease and the consumption of broccoli and its sprouts may be indicated.
 
 
INFLUENCE OF THE REDOX STATE ON THE ACTIVATION OF INFLAMMATORY AND APOPTOTIC PROTEINS IN EXPERIMENTAL HYPERTHYROIDISM
 
Description: Thyroid hormones are important for the development and maintenance of cellular functions, exerting influence on different body systems, mainly on the cardiovascular system. Hyperthyroidism is a pathology resulting from increased levels of thyroid hormones, and leads to increased cellular metabolism and oxygen consumption. The high oxygen demand generates an increase in ROS, with inability to remove them by antioxidants, leading to a situation of oxidative stress and redox imbalance, inducing the activation of transcription factors and cytokines, which lead to hypertrophy, inflammation and apoptosis. Chronic exposure to oxidative stress and redox imbalance induced by hyperthyroidism leads to hypertrophy of cardiomyocytes, and progression to heart failure. There are studies on hypertrophic, inflammatory and apoptotic responses mediated by proteins against the redox state, but more studies are needed to allow a greater understanding of what are the mechanisms involved in these processes, how the different signaling pathways are activated and how their actions are intertwined with disease progression.
 
 
THE EFFECTS OF DIFFERENT DOSES OF ANTHOCYAINS ON THE OXIDATIVE STRESS INDUCED BY HYDROGEN PEROXIDE IN CARDIOMYOCYTE CULTURES (H9c2)
 
 
Description: Cardiovascular diseases are caused by disorders of the heart and blood vessels, and include: coronary heart disease, cerebrovascular disease (stroke), hypertension, heart failure. They are among the leading cause of death worldwide. It is estimated that by 2030 the number of people who will die from cardiovascular diseases will reach 23.3 million people. It is already known that oxidative stress is closely related to cardiovascular disorders, as it plays a fundamental role in the pathophysiology of these diseases. In this sense, oxidative stress leads to an excessive production of reactive oxygen species (ROS) and their accumulation can contribute to the development of cardiovascular diseases. Studies suggest that agents with antioxidant power can protect the body against the undesirable activity of ROS, thus preventing the incidence of such diseases. Among the most diverse antioxidant agents, there are the anthocyanins belonging to the flavonoids, found in fruits and vegetables such as: blackberry, blueberry, grape. Currently, there is a growing interest in these antioxidants, due to the high intake by humans and their wide spectrum of potentially positive health effects in relation to the reduction of lipid peroxidation and LDL oxidation. In addition, it has a range of therapeutic benefits including antioxidant protection, genomic DNA integrity, cardio and neuroprotective effects, vasoprotectors, anti-inflammatory action, and anticancer properties.
 
 
EFFECTS OF THE BETA-BLOCKER BUCINDOLOL ON THE MODULATION OF RIGHT VENTRICLE REMODELING IN A MODEL OF MONOCROTALINE-INDUCED PULMONARY HYPERTENSION
 
 
EFFECTS OF TRAPIDIL ON THE INFLAMMATORY RESPONSE, REDOX STATE AND RIGHT VENTRICLE REMODELING IN THE MODEL OF MONOCROTALINE-INDUCED PULMONARY ARTERIAL HYPERTENSION
 
Description: Pulmonary hypertension (PH) is a comorbidity common to many heart and lung diseases. PH can lead to the development of pathological hypertrophy of the right ventricle and progression to Cor pulmonale. The use of animal models contributes extensively to the current understanding of the pathophysiology and investigation of experimental treatments in PH, with the model of monocrotaline (MCT), an alkaloid derived from the plant Crotalaria spectabilis, being widely used. In the progression of MCT-induced PH, we have cardiac involvement, with increased intraventricular pressure in the right ventricle, redox imbalance and the presence of an inflammatory infiltrate. The drug trapidil, already used in the post-coronary angioplasty clinic, has vasodilator, antithrombotic, anti-inflammatory and redox control properties. Thus, the project aims to verify possible beneficial actions of treatment with the drug during the progression of PH.
 
 
EVALUATION OF THE ANTIOXIDANT AND ANTI-INFLAMMATORY PROPERTIES OF PTEROSTILBENE IN THE EXPERIMENTAL MODEL OF RIGHT HEART FAILURE
 
Description: Introduction: Right heart failure, called Cor pulmonale, can be characterized by right ventricular hypertrophy, increased right intraventricular pressure, increased afterload and reduced ejection fraction, alterations that reduce the functional capacity of the right heart. It is known that oxidative and inflammatory mechanisms play an important role in the pathophysiology and progression of this disease. Thus, the administration of the phytochemical pterostilbene, a polyphenol with antioxidant potential, may represent a therapeutic alternative for the treatment of right heart failure. Our aim is to determine the toxicity, therapeutic dose and antioxidant capacity of pterostilbene, as well as its effect on functional, oxidative, inflammatory parameters and signaling pathways in the heart of rats with right heart failure induced by pulmonary hypertension.