Figure 7.

Graphical presentation of methodology and main findings. To evaluate the 5-aminoimidazole-4-carboxamide riboside (AICAR)-dependent effect on the aging male and female hearts, animals were treated with AICAR injections for 12 wk. Heart function was evaluated at time 0, 6, and 12 wk posttreatment, and then hearts were analyzed by histology and flow cytometry. In parallel experiments, AICAR effects on fibroblasts isolated from male and female hearts were assessed using two-dimensional (2-D) and three-dimensional (3-D) tissue culture. AICAR can reduce collagen turnover in the ECM and quench cardiac fibroblast activation through a Gli1-dependent pathway, improving age-related diastolic dysfunction in the female heart. By contrast, AICAR does not significantly improve fibroblast activation or cardiac function in the old male heart because of the blunted AICAR-dependent activation of AMPK.