Cardioprotective Heme Oxygenase 1‐PGC1α Signaling in Epicardial Fat Attenuates Cardiovascular Risk in Humans as in Obese Mice

Objective This study investigated whether levels of signaling pathways and inflammatory adipokines in epicardial fat regulate cardiovascular risks in humans and mice. Methods Epicardial fat was obtained from the hearts of patients with heart failure requiring coronary artery bypass surgery, and signaling pathways were compared with visceral fat. The genetic profile of epicardial and visceral fat from humans was also compared with genetic profiles of epicardial and visceral fat in obese mice. Left ventricular (LV) fractional shortening was measured in obese mice before and after treatment with inducers of mitochondrial signaling heme oxygenase 1 (HO-1)-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). An RNA array/heat map on 88 genes that regulate adipose tissue function was used to identify a target gene network. Results Human epicardial fat gene profiling showed decreased levels of mitochondrial signaling of HO-1-PGC1α and increased levels of the inflammatory adipokine CCN family member 3. Similar observations were seen in epicardial and visceral fat of obese mice. Improvement in LV function was linked to the increase in mitochondrial signaling in epicardial fat of obese mice. Conclusions There is a link between cardiac ectopic fat deposition and cardiac function in humans that is similar to that which is described in obese mice. An increase of mitochondrial signaling pathway gene expression in epicardial fat attenuates cardiometabolic dysfunction and LV fractional shortening in obese mice.