Abstract 16535: Conditional Knockout of the Mitochondrial 18-kDa Translocator Protein Limits Heart Failure
Introduction: Heart failure results in myocyte and mitochondrial death, and is characterized by abnormalities in mitochondrial calcium handling, energy production, and opening of the mitochondrial permeability transition pore (mPTP). The 18-kDa mitochondrial translocator protein (TSPO) has been shown to be significantly upregulated by heart failure in animals and in explanted hearts from patients, suggesting a vital role for this protein. Hypothesis: In the current experiments, we tested the hypothesis that conditional knockout of the TSPO using Cre inducible TSPO-floxed C57BL/6J mice would limit heart failure resulting from transverse aortic constriction (TAC).
Methods: Mice in 4 groups_wild-type (WT) sham, WT TAC, KO sham, and KO TAC_were monitored by weekly echocardiography for 8 weeks, followed by downstream experiments.
Results: TAC caused a 46±13% reduction in ejection fraction in WT mice, which was significantly lower in the KO mice (14±10%, P < 0.01, Figure). Strain analysis revealed a significant improvement in radial, longitudinal, and circumferential strain in KO TAC mice, supported by tissue histology finding of significantly less collagen in KO TAC mice. KO TAC mice showed lower heart to body weight and lung to body weight ratios, with no KO TAC mice showing signs of pulmonary edema. Calcium uptake experiment using Rhod-2 AM in isolated cells revealed that KO TAC mice had higher mitochondrial calcium uptake, a crucial finding since mitochondrial calcium uptake has been shown to play a role in energetics and mPTP opening.
Conclusion: Genetic modulation of the TSPO limits heart failure due to pressure overload, likely mediated by preserving mitochondrial calcium uptake and energy production, and possibly limiting mPTP opening. These data suggest that pharmacologic interventions that inhibit TSPO expression or function can limit heart failure at the sub-cellular level.
Author Disclosures: P. Thai: None. X. Lu: None. D. Daugherty: None. W. Deng: None. D.M. Bers: None. S. Schaefer: None.
- © 2015 by American Heart Association, Inc.