Cardiac-specific deletion of voltage dependent anion channel 2 leads to dilated cardiomyopathy by altering calcium homeostasis

Thirupura S. Shankar, Dinesh K. A. Ramadurai, Kira Steinhorst, Salah Sommakia, Rachit Badolia, Aspasia Thodou Krokidi, Dallen Calder, Sutip Navankasattusas, Paulina Sander, Oh Sung Kwon, Aishwarya Aravamudhan, Jing Ling, Andreas Dendorfer, Changmin Xie, Ohyun Kwon, Emily H. Y. Cheng, Kevin J. Whitehead, Thomas Gudermann, Russel S. Richardson, Frank B. Sachse, Johann Schredelseker, Kenneth W. Spitzer, Dipayan Chaudhuri and Stavros G. Drakos ()
Additional contact information
Thirupura S. Shankar: University of Utah
Dinesh K. A. Ramadurai: University of Utah
Kira Steinhorst: LMU Munich
Salah Sommakia: University of Utah
Rachit Badolia: University of Utah
Aspasia Thodou Krokidi: University of Utah
Dallen Calder: University of Utah
Sutip Navankasattusas: University of Utah
Paulina Sander: LMU Munich
Oh Sung Kwon: University of Connecticut
Aishwarya Aravamudhan: University of Utah
Jing Ling: University of Utah
Andreas Dendorfer: Ludwig-Maximilians Universität Munich
Changmin Xie: University of California
Ohyun Kwon: University of California
Emily H. Y. Cheng: Memorial Sloan Kettering Cancer Center
Kevin J. Whitehead: University of Utah School of Medicine
Thomas Gudermann: LMU Munich
Russel S. Richardson: Salt Lake City VA Medical Center
Frank B. Sachse: University of Utah
Johann Schredelseker: LMU Munich
Kenneth W. Spitzer: University of Utah
Dipayan Chaudhuri: University of Utah
Stavros G. Drakos: University of Utah

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24869-0

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