| First Author | Delgado C | Year | 2019 |
| Journal | Front Physiol | Volume | 10 |
| Pages | 40 | PubMed ID | 30792662 |
| Mgi Jnum | J:276430 | Mgi Id | MGI:6314079 |
| Doi | 10.3389/fphys.2019.00040 | Citation | Delgado C, et al. (2019) Gender-Dependent Alteration of Ca(2+) and TNFalpha Signaling in db/db Mice, an Obesity-Linked Type 2 Diabetic Model. Front Physiol 10:40 |
| abstractText | 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 Ca(2+) 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 (TNFalpha), than men. However, the gender-dependent regulation of Ca(2+) signaling in diabetes and its relationship with TNFalpha signaling are still unclear. Here, we analyzed TNFalpha signaling pathway and its role in Ca(2+) 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. TNFalpha increased [Ca(2+)]i transient amplitude and accelerated its decay without affecting SR Ca(2+) load or Ca(2+) spark frequency in cells from control mice. All TNFalpha effects on Ca(2+) handling were prevented by the inhibition of the ceramidase and the phospholipase A2 (PLA2). While the plasmatic level of TNFalpha was similar in male and female db/db mice, only male db/db hearts over-expressed both TNFalpha converting enzyme (TACE) and the protective TNFalpha receptors 2 (TNF-R2). TNFalpha receptor 1 (TNF-R1) expression, involved in negative inotropic response of TNFalpha, 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 [Ca(2+)]i transient amplitude associated to a drop of sarcoplasmic reticulum Ca(2+) load, not seen in female db/db mice. Interestingly, sustained incubation with TNFalpha did not restored Ca(2+) signaling alteration observed in male db/db mice but still induces an increase in Ca(2+) spark frequency as seen in control littermates. In cardiomyocytes from female db/db mice, TNFalpha had no visible effects on Ca(2+) handling. In conclusion, our study shows that the alteration of Ca(2+) signaling and TNFalpha, seen in db/db mice, is gender specific presenting an increase in TNFalpha cardio-protective pathway in male mice. |
