AUTHOR=Delgado Carmen , Gomez Ana-Maria , Samia El Hayek Magali , Ruiz-Hurtado Gema , Pereira Laetitia TITLE=Gender-Dependent Alteration of Ca2+ and TNFα Signaling in db/db Mice, an Obesity-Linked Type 2 Diabetic Model JOURNAL=Frontiers in Physiology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2019.00040 DOI=10.3389/fphys.2019.00040 ISSN=1664-042X ABSTRACT=

Cardiovascular complications are the primary death cause in type 2 diabetes, where inflammation can play a role. We, and others, have previously shown that, in diabetic cardiomyopathy, cardiac dysfunction is associated with Ca²⁺ mishandling. It is possible that diabetic cardiomyopathy differently affects men and women, as the latter present higher risk to develop heart failure and a higher plasmatic level of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα), than men. However, the gender-dependent regulation of Ca²⁺ signaling in diabetes and its relationship with TNFα signaling are still unclear. Here, we analyzed TNFα signaling pathway and its role in Ca²⁺ signaling dysfunction in male and female rodent models of type 2 diabetes linked to obesity (db/db mice) using confocal microscopy in freshly isolated cardiomyocytes. TNFα increased [Ca²⁺]_i transient amplitude and accelerated its decay without affecting SR Ca²⁺ load or Ca²⁺ spark frequency in cells from control mice. All TNFα effects on Ca²⁺ handling were prevented by the inhibition of the ceramidase and the phospholipase A2 (PLA2). While the plasmatic level of TNFα was similar in male and female db/db mice, only male db/db hearts over-expressed both TNFα converting enzyme (TACE) and the protective TNFα receptors 2 (TNF-R2). TNFα receptor 1 (TNF-R1) expression, involved in negative inotropic response of TNFα, was unchanged in both male and female db/db mice compared to controls. We found that male db/db mice cardiomyocytes presented a decrease in [Ca²⁺]_i transient amplitude associated to a drop of sarcoplasmic reticulum Ca²⁺ load, not seen in female db/db mice. Interestingly, sustained incubation with TNFα did not restored Ca²⁺ signaling alteration observed in male db/db mice but still induces an increase in Ca²⁺ spark frequency as seen in control littermates. In cardiomyocytes from female db/db mice, TNFα had no visible effects on Ca²⁺ handling. In conclusion, our study shows that the alteration of Ca²⁺ signaling and TNFα, seen in db/db mice, is gender specific presenting an increase in TNFα cardio-protective pathway in male mice.