Figure 1. Generating a chemogenetic model of heart failure
caused by oxidative stress. A) A recombinant cardiotropic
adeno-associated virus serotype 9 (AAV9) expressing a yeast D-amino acid
oxidase (DAAO) under control of the cardiac-specific cTnT promoter was
constructed and injected via tail vein into rats or mice. B) 4 weeks
following infection with either control AAV9 or DAAO-AAV9, the DAAO
substrate D-alanine was provided in the animals’ drinking water.
D-alanine feeding leads to the activation of DAAO, which catalyzes the
oxidation of D-alanine to its corresponding α-keto acid (pyruvate),
along with equimolar generation of H2O2and ammonia C) The effects of in vivo generation of oxidative
stress in cardiac myocytes were monitored weekly by echocardiography. D)
After 4 weeks of chemogenetic oxidative stress, the DAAO-infected
animals develop severe cardiac dysfunction, with ventricular dilation
and decreased ejection fraction. Shown are representative
echocardiographic images of the left ventricle of control AAV9 (above)
or DAAO-AAV9-infected rats (below).
Modified from Steinhorn B, Sorrentino A, Badole S, Bogdanova Y,
Belousov, V., and Michel, T. (2018) Chemogenetic generation of hydrogen
peroxide in the heart induces severe cardiac dysfunction, Nature Commun
9, 4044 .