Abstract 4: Transient Receptor Potential Melastatin 7 Cation Channel (TRPM7) Kinase Domain - a New Player in Angiotensin II-induced Hypertension and Cardiac Hypertrophy
Transient receptor potential melastatin 7 (TRPM7) cation channel is a unique protein that has the dual ability to act as a channel to regulate transmembrane Mg2+ transport and also as a kinase to promote cellular signaling. Despite increasing awareness of the importance of Mg2+ in cardiovascular biology nothing is known about TRPM7 and its kinase domain in the pathophysiology of hypertension. We previously demonstrated that Ang II regulates TRPM7 in vitro. Here we studied TRPM7 kinase-deficient mice to explore the role of the TRPM7 kinase domain in Ang II-induced hypertension. TRPM7 kinase deficient mice (TRPM7+/-) and wild type (WT) counterparts were infused with Ang II (400 ng/kg/min; minipumps) for 4 weeks. Blood pressure (BP) was measured by tail cuff. Vascular reactivity and structure studies were performed by myography in mesenteric arteries. Although baseline BP tended to be higher in TRPM7+/- versus WT mice (127 ± 6.0 vs 119 ± 2.2 mmHg), significance was not achieved. TRPM7+/- mice displayed earlier onset of BP increase by Ang II (2 weeks; WT-Ang II: 145 ± 5 vs TRPM7+/-Ang II: 178 ± 9; mmHg). After 4 weeks, BP was significantly higher in TRPM7+/- (174 ± 10 mmHg) than in WT mice (147 ± 8 mmHg). Ang II-induced hypertension was associated with cardiac hypertrophy, an effect that was exaggerated in TRPM7+/- mice (WT: 4.4 ± 0.1; WT-Ang II: 5.0 ± 0.2; TRPM7+/-: 4.5 ± 0.1; TRPM7+/-Ang II: 5.7 ± 0.1 g/body weight). Mesenteric arteries from Ang II-infused TRPM7+/- mice exhibited decreased sensitivity to acetylcholine (pD2; WT-Ang II: 7.6 ± 0.3 vs. TRPM7+/-Ang II: 6.7 ± 0.4), and reduced maximal relaxation compared to WT mice (WT-Ang II: 88 ± 8% vs TRPM7+/-Ang II: 59 ± 10%). Ang II induced a leftward shift in the stress-strain relationship for both WT and TRPM7+/- mice in a similar fashion. Plasma analysis revealed that TRPM7+/- mice were hypomagnesemic, and that Ang II increased Mg2+ levels to a greater extent in WT than in TRPM7+/- mice (WT: 0.65 ± 0.02; WT-Ang II: 0.74 ± 0.04; TRPM7+/-: 0.60 ± 0.01; TRPM7+/-Ang II: 0.64 ± 0.02; mmol/L). In conclusion, our findings demonstrate that hypertension, cardiac hypertrophy and endothelial dysfunction are exaggerated by Ang II in TRPM7+/- hypomagnesemic mice, suggesting a novel role for TRPM7 kinase domain in cardiovascular pathophysiology.
- © 2013 by American Heart Association, Inc.