Abstract 9376: TRPM77 Knockdown Prevents Hypomagnesemia-Induced Oxidative Stress and Cardiac Diastolic Dysfunction

Abstract

Introduction: Our previous study has shown that 6-week low-Mg diet-induced hypomagnesemia results in mitochondrial dysfunction, cardiac diastolic dysfunction, and seizure-related death. Transient receptor potential cation channel subfamily M 7 (TRPM7) is a Mg transporter with both channel and kinase function located in the plasma membrane. We investigated the role of TRPM7 in hypomagnesemia-associated changes. Methods: For cardiac-specific knockdown of TRPM7, pAAV[miR30]-cTnT>EGFP:Scramble-shRNA as control (Con) and pAAV[miR30]-cTnT>EGFP:TRPM7 shRNA as TRPM7 knockdown (T7KD) were injected into mice through the jugular vein at 10 weeks old. One week later, mice were fed with a normal diet (nlMg, 2000 mg/kg Mg) or a low-Mg diet (HypoMg, 15-30 mg/kg Mg) for 4 weeks. Results: TRPM7 was increased significantly in wild type mouse hearts under the low-Mg diet (1.45±0.18-fold of mice with normal diet, P<0.01). We therefore knocked down TRPM7 in the mouse heart to see if HypoMg-induced changes could be prevented. After 4 weeks of low-Mg diet, both Con and T7KD mice had hypomagnesemia with significantly decreased serum Mg levels (0.37±0.03 and 0.45±0.10 mM, respectively, vs 1.05±0.04 mM of Con-nlMg). All T7KD mice showed significantly decreased TRPM7 protein levels in the heart tissue (<30% of Con-nlMg, P<0.01). Cardiac diastolic dysfunction (E/e’) was prevented in T7KD-HypoMg mice (E/e’=16.2±1.9 vs. 20.7±1.5 of Con-HypoMg). Increased total protein oxidation (measured with nitro-tyrosine immunoprecipitation) in Con-HypoMg heart tissue (1.61±0.09-fold increase, P=0.045 vs. Con-nlMg) was normalized in the T7KD-HypoMg group (1.18±0.09-fold of Con-nlMg, P=0.45 vs. Con-nlMg). Conclusions: TRPM7 was upregulated in hypomagnesemia in hearts and its knockdown prevented hypomagnesemia-induced cardiac diastolic dysfunction and increased oxidative stress.