Abstract 19564

Objective: The mitochondrial calcium (_mitoCa²⁺) microdomain has been under intense investigation due to its significant influence on both energy production and cell death, both of which are suggested to contribute to the development of heart failure (HF). To examine the contribution of _mitoCa²⁺ signaling in HF pathology, we developed mice with conditional overexpression of the _mitoNCX candidate gene (Slc8b1, also known as NCLX), using the tetracycline-controlled cardiomyocyte-restricted expression system (αMHC-tTA, dox-off). Mice were maintained on doxycycline-containing chow until weaning after which time removal allowed expression of the transgene.

Results: αMHC-tTA x TRE-_mitoNCX mice (_mitoNCX-Tg) displayed a 3-fold increase in _mitoNCX protein expression as compared to tTA littermate controls with no compensatory changes in the expression of other mitochondrial calcium channels. Examination of _mitoCa²⁺ dynamics using multiple experimental systems revealed that overexpression of _mitoNCX increased the rate of _mitoCa²⁺ efflux from the matrix. Next, we subjected mice to two different surgical models of heart failure; myocardial infarction (permanent ligation of the left coronary artery, MI) and pressure-overload induced failure (transverse aortic constriction, TAC). Following the surgical induction of HF mice underwent weekly echocardiographic measurements of left ventricular (LV) function, dimensions and strain analysis. At baseline, _mitoNCX-Tg mice displayed similar LV function and structure as tTA controls. However, following both TAC and MI _mitoNCX-Tg mice exhibited significantly greater LV function (shown below as percent fractional shortening, %FS) and a preservation of LV structure as compared to tTA controls.

Conclusions: These findings suggest that enhancing _mitoCa²⁺ efflux during the development of HF is advantageous and represents a novel therapeutic approach.