Figure 6. Knockdown of GR and KLF15 in db/db hearts in vivo blocks the ZT0 prednisone effects.

(A) Representative Western blot showing knockdown of GR and KLF15 at 12 weeks after transduction and ZT0 prednisone regimen start, as well as blunting of the treatment effect on ADIPOR1, MPC1, and MPC2 protein level upregulation in hearts of db/db mice transduced with the knockdown vectors compared with mice transduced with scramble vectors. (B and C) Knockdown MyoAAV combination blocked the treatment effects on diastolic dysfunction (E/e′), stroke volume, cardiac hypertrophy (heart weight/tibia length), and insulin-driven glucose uptake (2DG6P). (D) Treatment increased glucose-fueled respiration (oxygen consumption rate, OCR) in permeabilized cardiac biopsies and pyruvate-fueled respiration (respiratory control ratio, RCR) in isolated myocardial mitochondria in scramble-, but not knockdown-transduced, hearts. Data are presented as mean ± SEM; histograms also show individual mouse values. n = 5 ♂/group. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001 by 2-way ANOVA with Šidák’s post hoc test.