Objectives: 

Voltage-gated T-type Ca2+ channels (T-channels) are normally expressed during embryonic development in ventricular myocytes but are undetectable in adult.Interestingly, T-channels are reexpressed in some pathological conditions associated with hypoxic episodes, although the underlying mechanisms are not known.

Materials: 

Cell cultures from adult and neonatal ventricular myocytes were used to study the hypoxic signalling pathway involved in T-channels upregulation. To analize expression of different genes and proteins we used RT-qPCR and western blot analysis. We perform measurements of RhoA using the G-LISA technique. T-channels currents were recorded using the whole-cell configuration of the patch-clamp technique. XTT Kit was used to analyze cell proliferation.

Results: 

We report here that Cav3.2 subunit of T- channels is highly induced by hypoxia in cardiomyocytes. This effect is time- and dose-dependent, and is accompanied by an increase in the density of the T- channel currents recorded in patch-clamped cells. HIF-1a seems to be involved in the T-channel upregulation. In addition, we demonstrated that low oxygen conditions might modulate HIF-1a expression through the Rho/ROCK signaling pathway. We show that hypoxia increased RhoA activity as well as RhoA and ROCK protein levels. Furthermore, RhoA and ROCK inhibitors, inhibited hypoxia-induced HIF-1a expression and blocked the Cav3.2 mRNA induction. Our results also demonstrate that the upregulation of T-channels by hypoxia, via HIF-RhoA/ROCK, regulates proliferation in ventricular myocytes.

Conclusions: 

These results suggest that hypoxia produces a decrease in HIFa degradation via activation of the Rho/ROCK signaling in ventricular myocytes. These events regulate T-channel expression in hypoxic conditions. Moreover, T-channels upregulation (vía HIF-1a-RhoA/ROCK) increases proliferation in ventricular myocytes, suggesting that this signaling pathway could play a role in the pathogenesis of ischemic cardiomyopathy.