Obesidade induzida por dieta de cafeteria e suas implicações cardiovasculares em camundongos sobreviventes à sepse: o envolvimento de NOS, NO e COX

Abstract

Sepsis survivors have an increased risk of development of cardiovascular diseases (CVDs). Sepsis outcomes, including the development of CVDs, depend on the complex interaction between pathophysiological alterations triggered by sepsis and pre-sepsis health status, which includes the existence of underlying chronic diseases. Obesity is an important risk factor for CVDs and its prevalence has considerably increased in the developed countries, where sepsis is one of the most important causes of mortality. Therefore, the coexistence of both conditions has become frequent in clinical practice. However, the impact of obesity on the cardiovascular outcomes of sepsis remains unclear. Thus, the aim of this study was to investigate how the cafeteria (CAF) diet-induced obesity influences the cardiovascular responses in mice that survived experimental sepsis. The results showed that CAF diet-induced obesity did not influence morbimortality from sepsis. However, it caused adiposity and metabolic alterations in the sepsis survivors animals, characterized by an increase of adiposity associated with hypercholesterolemia and hyperleptinemia. Furthermore, the CAF diet-induced obesity altered the cardiovascular responses in sepsis survivors. The analyses of electrocardiogram demonstrated that the CAF-CLP group animals were protected from impairments in the important segments of electrocardiogram; however, they showed narrowing of QRS interval, which can predispose to arrhythmias. The heart and cardiomyocytes isolated from the CAF-CLP group showed increased basal intrinsic function. However, under pharmacological stress induced by isoprenaline, the cardiac responsiveness of the CAF-CLP group was significantly impaired. CAF diet- induced obesity caused reduction in the phenylephrine-induced vasoconstriction that was exacerbated in the CAF-CLP group. Aortic hyporeactivity in the CAF-CLP group was essentially mediated by endothelium pathways involving both an impairment of contractile stimulus and an increase of relaxation stimulus. The impairment of contractile stimulus was triggered by the reduction of ERK 1/2 activation associated with decreased production of vasoconstrictors prostanoids derived from COX, while the increase of relaxation stimulus was triggered by the eNOS activity leading to NO production, and consequently sGC activation. Although it did not influence the morbimortality from sepsis, CAF diet-induced obesity improved the animals morbimortality when faced with a secondary infection with Aspergillus fumigatus. Taken together, our findings showed that CAF diet-induced obesity alters the cardiovascular responses in sepsis survivors, characterized by increased intrinsic cardiac function and impaired aortic hyporesponsiveness. Despite these adaptive alterations, CAF diet-induced obesity does not influence morbimortality from sepsis; however it seems to be protective against a new infectious insult.