Abstract
Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Through this unique role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure.
Highlights
Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling
Our results suggest that deletion of Voltage-dependent anion-selective channel protein 2 (VDAC2) in the myocardium during development causes dilated cardiomyopathy (DCM) and eventually leads to increased mortality
sarcoplasmic endoplasmic reticulum calcium ATPase 2a (SERCA2a) and NCX1 are the two main channels involved in cytosolic calcium clearance during diastole and we showed that these protein levels are significantly reduced in VDAC2-KO (Fig. 2f and l)
Summary
Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Electrical excitation of the membrane causes L-type calcium channels (LTCC) to open and a small amount of calcium enters the cell which binds to ryanodine receptor 2 (RyR2) and triggers the sarcoplasmic reticulum (SR) to release some of its calcium reserve This release results in an overall increase in the cytosolic calcium which binds to troponin thereby facilitating cellular contraction. Reintroduction of VDAC2 in 6-week-old KO mice using an adeno-associated virus 9 (AAV9) vector seemed to partially rescue the cardiomyopathy phenotype suggesting a plausible role of VDAC2 as a therapeutic target in clinical HF To evaluate this hypothesis, we took a gain-of-function approach and measured the effects of VDAC2 agonist efsevin in murine tissue from failing hearts: in line with the HF phenotype induced by VDAC2-KO, efsevin enhanced contractile force in failing myocardium from a murine pressure-overload model establishing VDAC2 as a promising target for HF
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