Details

Autor(en) / Beteiligte

• Alves-Lopes, Rhéure
• Montezano, Augusto C
• Neves, Karla B
• Anagnostopoulou, Aikaterini
• Lacchini, Silvia
• Touyz, Rhian M

Titel

Abstract P219: Vascular Cross-talk Between Redox and Calcium Signaling in Hypertension Involves Transient Receptor Potential Melastatin 2 Channel Activation

Ist Teil von

• Hypertension (Dallas, Tex. 1979), 2017-09, Vol.70 (suppl_1)

Erscheinungsjahr

2017

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Abstract only The transient receptor potential melastatin 2 cation channel (TRPM2) is redox-sensitive and promotes Ca 2+ influx after H 2 O 2 activation through oxidative modification and PARP-ADPR-dependent mechanisms. TRPM2 also regulates Na + influx, and by increasing [Na + ]i interferes with the Na + -Ca 2+ exchanger (NCX) inducing reverse mode action, promoting Ca 2+ influx. These processes may be driven by Nox4-derived H 2 O 2. We tested the hypothesis that vascular dysfunction in hypertension involves oxidative stress-induced TRPM2 activation through H 2 O 2 production, which in turn promotes Ca 2+ influx. Mesenteric arteries isolated from wildtype (WT), LinA3 (mice expressing human renin with Ang II-dependent hypertension), Nox4 -/- and LinA3/Nox4 -/- mice and vascular smooth muscle cells (VSMCs) from hypertensive and normotensive patients were used. Arteries from hypertensive LinA3 mice, exhibit increased U46619-induced vasoconstriction versus WT mice (Emax - LinA3 vs WT: 9.37 ± 0.51 vs 6.79 ± 0.29), an effect attenuated by olaparib (PARP-ADPR inhibitor) and 2-APB (TRPM2 blocker) and also increased mRNA expression (Fold change - related to control) of NOX4 (3.05 ± 0.30), TRPM2 (1.38 ± 0.24), NCX (1.973 ± 0.34) and salt inducible kinase 1 (1.833 ± 0.12) and sodium-potassium pump (1.43 ± 0.16), which are activated when intracellular levels of Na + rise beyond a critical point. These events seem to be regulated by NOX4, since they were not observed in mesenteric arteries from LinA3/Nox4 -/- mice. Ang II-induced Ca 2+ influx is potentiated in VSMCs from hypertensive patients (AUC-Ex490/Em535: normotensive: 15400±917.5 vs hypertensive - 22460±2388), a response followed by increased generation of O 2 - and H 2 O 2 in cells from hypertensive patients. These ROS effects were attenuated by catalase, and 2-APB, 8-br and olaparib (TRPM2 inhibitors) and benzamil, KB-R7943 and YM244769 (NCX inhibitors). Our data indicate that TRPM2 ion channel activation contributes to redox-sensitive vascular dysfunction in hypertension. These findings suggest that dysregulation of TRPM2-NOX4-derived ROS and NCX may contribute to redox- and Ca 2+ signalling important in vascular function in hypertension. TRPM2 may be a point of cross-talk between ROS and Ca 2+ signalling.