Yuanhang Zhao, University of Utah
Heart failure (HF) is a progressive syndrome that is one of the leading causes of hospitalization globally. Recent clinical investigations have revealed that mechanical unloading via the implantation of a left ventricular assist device (LVAD) proves to be an effective therapeutic intervention that leads to substantial improvement of cardiac function in subpopulation of HF patients. To elucidate pathways involved in the LVAD-mediated myocardial recovery process, cardiac tissue is collected from patients with LVAD implants to distinguish a difference between those who exhibit LVAD-induced myocardial functional recovery versus patients with no signs of functional improvement post-implant. Data collected from patients with failing hearts indicated significant differences in VDAC2 phosphorylation following phosphopreteomic analysis. Voltage-dependent anion channels (VDACs) have long been suggested to play a role in the mitochondrial permeability transition pore. Of the three isoforms of VDAC, only the total knockout of VDAC2 causes early embryonic lethality and demonstrates a nonredundant function in mouse models. Additionally, a previous study demonstrated zebrafish with a defect in the Na+/Ca2+ (NCX) exchanger resulting in irregular contractions are phenotypically rescued by the overexpression of VDAC2 following injections of in vitro synthesized VDAC2 mRNA or with efsevin, a small molecule that activates VDAC2. I investigated the role of VDAC2 in cardiac physiology using mice with a targeted homozygous deletion of VDAC2 in cardiomyocytes via Cre-lox recombination. Preliminary results from echocardiograms and statistical analysis of cardiac physiology show that cardiac specific tamoxifen induced-KOs of VDAC2 in the adult murine heart yield no significant anomaly in cardiac function. However, it is unknown if stressors or pressure overload will result in maladaptive responses in these mice. Cardiac-specific VDAC2 KO mice during late embryonic development using MHC-Cre show symptoms of cardiac arrhythmia, hypertrophy, and occasional postnatal sudden death. This suggests VDAC2 may play a critical role in regulating Ca2+ transient homeostasis and excitation-contraction coupling in all cardiomyocytes or electrical conduction system as a consequence of its role in mitochondrial Ca2+ uptake. The role of VDAC2 in mitochondrial permeability transition pore may also lead to cardiac remodeling and structural anomaly during development in VDAC2 deficient mice.