AAV DJ/8-GFP

The heart utilizes multiple adaptive mechanisms to maintain pump function. Compensatory cardiac hypertrophy reduces wall stress and oxygen consumption, thereby protecting the heart from acute increases in blood pressure. Yes-associated protein 1 (YAP), a nuclear effector of the Hippo pathway, is activated and mediates compensatory cardiac hypertrophy induced by acute pressure overload (PO). In this study, YAP promoted glycolysis by upregulating glucose transporter 1 (GLUT1), which in turn led to the accumulation of intermediates and metabolites of glycolytic, auxiliary, and supplementary pathways during acute PO. In the presence of acute PO, cardiac hypertrophy was suppressed and heart failure was exacerbated in YAP haploinsufficient mice. However, normalization of GLUT1 rescued the deleterious phenotype. PO induced the accumulation of glycolytic metabolites in a YAP-dependent manner, promoting cardiac hypertrophy. YAP upregulates the GLUT1 gene by interacting with TEA domain family member 1 (TEAD1) and HIF-1α in cardiomyocytes. Thus, YAP induces compensatory cardiac hypertrophy by activating the Warburg effect.

Here, researchers performed a GLUT1 rescue experiment, in which mice were injected with either AAV-DJ/8-GFP (AAV-control) or AAV-DJ/8-GLUT1 (AAV-GLUT1) and, after 2 weeks, subjected to either sham operation or TAC. Studies confirmed that AAV-GLUT1 significantly increased GLUT1 expression in the heart (Figure 1A and B). After 7 days of PO, mice were subjected to echocardiographic analysis and sacrificed. AAV-GLUT1 successfully rescued GLUT1 upregulation in YAPch-KO mice after 7 days of TAC (Figure 1C and D). Fractional shortening (FS, %), a measure of systolic function (Figure 1E and F), LV end-diastolic internal dimension (LVIDd), a measure of LV dilation (Figure 1E and G), and lung weight/tibia length (LungW/TL), a measure of lung congestion (Figure 1H), which is a sign of heart failure, were not affected in either AAV-control– or AAV-GLUT1–injected control mice. TAC-induced left ventricular systolic dysfunction and left ventricular dilation were observed in AAV control-injected YAPch-KO mice (Figure 1E-G). TAC-induced systolic dysfunction, left ventricular dilation, and pulmonary congestion were not evident in YAPch-KO mice injected with AAV-GLUT1 (Figure 1E-H).

Figure 1. Overexpression of GLUT1 ameliorates cardiac dysfunction in YAPch-KO mice during acute PO. (Kashihara T, et al., 2022)