Supplementary MaterialsS1 Raw images: (PDF) pone

Supplementary MaterialsS1 Raw images: (PDF) pone. but not male MLEC. In contrast, treatment with mitochondrial respiratory Complex III inhibitor Antimycin A (AA, 50M) mediated severe necrosis specifically in male MLEC, while female cells again responded primarily by apoptosis. The same effect with female cells responding to the stress by apoptosis and male cells responding by necrosis was confirmed in starved pulmonary endothelial cells isolated from human donors. Elevated necrosis seen in male cells was associated with a significant release of damage-associated alarmin, HMGB1. No stimuli induced a significant elevation of HMGB1 secretion in females. We conclude that male cells appear to be protected against mild stress conditions, such as hypoxia, possibly due to increased mitochondrial respiration. In contrast, they are more sensitive to impaired mitochondrial function, to which they respond by necrotic death. Necrosis in male vascular cells releases a significant amount of HMGB1 that could contribute to the pro-inflammatory phenotype known to be associated with the male gender. 1. Introduction Sex is a known contributing factor to many cardiovascular diseases. Due to the protective effects of female sex hormones females are generally found to be less affected or have a better prognosis. However, in pulmonary arterial hypertension (PAH), the female gender is known to be associated with a higher susceptibility to the disease. This effect, known as the estrogen paradox, is under a close investigation by many research groups [1C4]. Although males have a significantly lower prevalence in PAH, they show a conspicuously worse survival prognosis [5, 6]. The poor survival of male PAH patients is commonly attributed to the progressive development FLN of right ventricle (RV) failure [6], possibly due to the absence of cardioprotection mediated by female hormones. Besides, it has been recently discovered that the male gender is associated with a considerably more severe inflammatory profile compared to females [7]. Thus, many inflammatory conditions, including acute respiratory distress Deltasonamide 2 (TFA) syndrome (ARDS) [8], meningitis [9], and myocarditis [10] were reported to have more severe forms and poorer prognosis in males. Males commonly have a worse recovery from surgical procedures [11], show higher production of inflammatory markers [12], and a higher rate of infection-induced mortality in general [7]. Since inflammation is an established contributor to PAH pathogenesis, the increased inflammatory reactions seen in males could significantly contribute to the PAH progression and outcome. Indeed, the inflammation-associated forms of PAH, such as HIV-associated PAH, have an inverted male to female ratio 7.7:1 [13]. Our previously published studies that used Sugen/Hypoxia-induced rat model of PAH showed that male rats have worse survival, more severe intravascular and perivascular inflammation, and activation of inflammatory pathways in lungs [14, 15]. None of these changes were evident in PAH female rats. The less pronounced inflammatory changes in PAH females were recently associated with the increased functionality of regulatory T cell (Treg) [16]. The ability of T regs to suppress over-activation of the immune system, inflammation, and perivascular infiltration of pulmonary vessels with inflammatory cells protects females Deltasonamide 2 (TFA) against PAH. Although sex-mediated effects are classically viewed through the prism of sex Deltasonamide 2 (TFA) hormones, the last research [16] and a few other recent reports [17] suggest the presence of nonhormonal mechanisms that are responsible for manifestation of the sex difference. Therefore, in this study, we were interested in investigating whether pulmonary endothelial cells omitted from the effects of sex hormones or interactions with other cell types will still preserve the sex difference. Indeed, we.