Abstract 13843: Cardiac-targeted Trpm7 Deletion Generate Phenotypes Through Perturbations In Myocardial Development
Trpm7 is a divalent permeant channel-kinase expressed robustly in heart, particularly during embryonic development. We showed previously that global deletion of Trpm7 results in early embryonic lethality (∼E7.5), suggesting a critical role in embryogenesis. To study the role of Trpm7 in cardiac physiology we generated 3 lines of cardiac-targeted knock-out (KO) mice that delete Trpm7 at different stages of cardiac development and in adulthood by crossing the floxed Trpm7 mouse (Trpm7fl/fl) with TnT-Cre (E9), αMHC-Cre (E18), and tamoxifen-inducible MerCreMer lines. Trpm7 deletion was confirmed in KO at the level of genomic DNA (PCR) and by elimination of Trpm7 currents in αMHC-Cre ventricular cells (0.003 ± 0.033 pA/pF @100 mV, n = 19) compared to wild-type controls (WT) (4.0 ± 0.8 pA/pF @100 mV, n = 11). Trpm7 deletion early in cardiac development (TnT-Cre) results in embryonic lethality by E10–11 that cannot be rescued by Mg supplementation. By contrast, Trpm7 deletion late in cardiac development (αMHC-Cre) generates viable mice that exhibit sinus tachycardia of 80–100 bpm over WT (Mean 24hr HR: KO = 659 ± 15 bpm; WT = 579 ± 15 bpm, P < 0.01) as assessed by telemetry in conscious-freely moving mice. This sinus tachycardia occurs despite unchanged ventricular morphology and function, identical myocardial Mg content and equivalent levels of circulating serum catecholamines, suggesting an increase in intrinsic heart rate (HR) as opposed to compensatory/regulatory changes. Indeed, both in vivo ECGs with ganglionic blockade and ECGs from isolated perfused hearts confirm that intrinsic HR are elevated by ∼15% in αMHC-Cre KO mice compared to WT. Trpm7 current densities in isolated WT sino-atrial pacemaker cells (32.0 ± 6.0 pA/pF, n = 6) are noted to be 8-fold higher than in WT ventricular cardiomyocytes and entirely eliminated in αMHC-Cre KO sino-atrial cells. Furthermore, Trpm7 deletion after completion of cardiac development (adult) using the tamoxifen-inducible MerCreMer line generates completely normal hearts with no evidence of sinus tachycardia. Overall, these data suggest that cardiac phenotypes resulting from Trpm7 deletion arise from perturbations in cardiac development as opposed to disrupting an active role of Trpm7 in basal myocardial function.
- © 2010 by American Heart Association, Inc.