Nous factors implicats en la patologia cardíaca i l’obesitat

Abstract

Cardiovascular diseases are one of the leading causes of mortality in industrialized countries and are caused by genetic factors, environmental factors or comorbidities. This thesis is focused on three cardiovascular risk factors such as hypertension, alcoholism and obesity. These pathologies are mainly characterized by hypertrophy and cardiac fibrosis. In recent last years, cardiomyokines have been described as cardioprotective factors against pathological stimuli. One of the most important cardiomyokines is Fibroblast growth factor 21 (FGF21). FGF21 is released by the heart under cardiac stress situations where acts in a autocrine or paracrine manner protecting cardiomyocytes against inflammation, oxidative stress and apoptosis. FGF21 has been described as a protective factor against cardiac hypertrophy, atherosclerosis, ischemia and other cardiac pathologies. In the first part this thesis has studied the role of FGF21 in hypertensive and alcoholic cardiomyopathy. It has been identified that FGF21 gene expression in heart and its circulating levels are induced in response to hypertension, and that FGF21 acts at cardiac level protecting against cardiac fibrosis. Its protective effect has been confirmed in newborn animals treated with FGF21 where cardiac fibrosis was reversed. Moreover, this protective effect on cardiac fibrosis is due to a direct effect of FGF21 on cardiac fibroblasts. It has also been identified that FGF21 gene expression in heart and its circulating levels are induced in response to chronic alcohol consumption. In contrast, lack of FGF21 altered cardiac metabolism, oxidative stress and mitochondrial damage in animals subjected to chronic alcohol consumption. In addition, a positive correlation between myocardial FGF21 levels and oxidative stress have been found in alcoholic patients suggesting a role of FGF21 in the activation of antioxidant defenses during alcoholic cardiomyopathy. On the other hand, this thesis has avaluated two proteins involved in the regulation of energy expenditure through brown adipose tissue (BAT). BAT is the main energy-consuming tissue in mammals. It is considered that BAT may play a role in protecting against obesity. Metrnl is a metabolic regulator that promotes TAM activation while Oncostatin M (OSM) inhibits it. In the last part of this thesis we have studied the role of Metrnl and OSM in obese patients undergoing bariatric surgery. Metrnl circulating levels increase progressively after bariatric surgery while OSM levels decrease in obesity patients undergoing bariatric surgery. This suggests that bariatric surgery modulates circulating levels of these two proteins in an opposite manner in order to activate BAT and promote energy expenditure in these obese patients. In summary, FGF21 appears to play an important role in the protection of cardíac fibrosis induced by hypertensive cardiomyopathy. In addition, FGF21 also appears to play an important role in activating antioxidant defenses during alcoholic cardiomyopathy. Lastly, Metrnl and OSM could be regulated during bariatric surgery to promote energy expenditure activation and protect against obesity.