AAV9-cTNT-GFP

Cardiac hypertrophy is a major risk factor for congestive heart failure, a leading cause of morbidity and mortality. Mitochondrial dysfunction is a hallmark of many human diseases, including cardiac hypertrophy and heart failure. F1Fo-ATP synthase catalyzes the final step of oxidative energy production in mitochondria. Oligomycin sensitivity conferring protein (OSCP) is a key component of F1Fo-ATP synthase and plays a crucial role in mitochondrial energy metabolism. Here, researchers found that impaired OSCP expression in the heart coexists with mitochondrial dysfunction in hypertrophic hearts. They used cardiac-specific, adeno-associated virus-mediated OSCP gene therapy to treat mice subjected to pressure overload caused by transverse aortic coarctation (TAC). OSCP gene therapy protected TAC mice from cardiac dysfunction, cardiomyocyte hypertrophy, and fibrosis. OSCP gene therapy also enhanced mitochondrial respiratory capacity in TAC mice. OSCP gene therapy consistently attenuated reactive oxygen species and mitochondrial permeability transition pore opening in hypertrophic hearts. In conclusion, adeno-associated virus type 9-mediated cardiac-specific OSCP overexpression can protect the heart by improving mitochondrial function.

The TAC hearts were substantially enlarged compared with sham hearts, but enlargement was less pronounced in AAV9-cTNT-OSCP than AAV9-cTNT-GFP treated mice (Figure 1A). The heart-to-body-weight ratio (HW/BW) and heart-to-tibia length ratio (HW/TL) were decreased in AAV9-cTNTOSCP compared with the AAV9-cTNT-GFP treatment group (Figure 1B and C). Real-time PCR assay showed that the transcript expression of ANF and BNP was significantly more elevated in the hearts of AAV9-cTNT-GFP than AAV9-cTNT-OSCP treated group (Figure 1D). In addition, histological staining of H&E, Masson Trichrome, and Sirius red on heart sections showed a smaller cross-sectional area of cardiomyocytes (Figure 1E) and less pronounced fibrosis (Figure 1F and G) in AAV9-cTNT-OSCP-treated mice than AAV9-cTNT-GFP-treated mice after TAC. Transmitted electron microscopy imaging of heart sections showed improved mitochondrial integrity in the ultrastructure of cardiomyocytes in AAV9-cTNT-OSCP-treated hearts compared with AAV9-cTNT-GFP-treated hearts (Figure 1E). After TAC, AAV9-cTNT-GFP-treated hearts showed disruption of the mitochondrial network, matrix loss, vacuolation, swelling, and reduced mitochondrial cristae compared with AAV9-cTNT-OSCP-treated hearts (Figure 1E). These results indicate that OSCP gene therapy protects the heart from pressure overload hypertrophy and pathological development.

Figure 1. AAV9 mediated OSCP overexpression improves cardiac dysfunction in pressure overload-induced hypertrophied hearts. (Guo Y, et al., 2020)