IN PATIENTS UNDERGOING ON-PUMP CORONARY ARTERY GRAFTING (CABG), INCREASED ATRIAL FARNESOID X RECEPTOR SIGNALING IS ASSOCIATED WITH ATRIAL MYOCARDIAL APOPTOSIS COMPARED TO OFF-PUMP CABG

Abstract

The Farnesoid X receptor (FXR) a member of the nuclear receptor superfamily of ligand-activated transcription factors that functions as an endogenous sensor for bile acids, is expressed mainly in the liver, adipose tissue and intestine. Recent evidence suggests that FXR also acts as a novel functional receptor in murine myocardium, regulating apoptosis and contributing to ischaemia/reperfusion injury. The potential expression and possible function of FXR in the diseased human heart remains largely unknown. The present study aimed to examine the levels of FXR, its ligand proliferator-activated receptor gamma coactivator 1α (PGC1α), its target small heterodimer protein (SHP) at the mRNA and protein levels and parameters of apoptosis (pro-apoptotic BAX/anti-apoptotic BCL2 mRNA ratio) in 59 patients undergoing on- pump CABG and 31 patients off-pump CABG. The on-pump group consisted of 15 women and 44 men with a mean ± S.E. age of 66.57±1.78 and 64.02±1.25 years respectively, and the off- pump patients consisted of 3 women and 28 men with a mean + S.E. age of 69.00±2.08 and 63.46± 1.66 years respectively. We analyzed FXR, SHP, BAX and BCL2 mRNA expression by quantitative Real Time PCR using 18s as an internal control for standardization in right atrial biopsies taken before aortic occlusion and after reperfusion during CABG. FXR and SHP protein was determined by Western blot. FXR mRNA (fold change) post CABG was significantly (p<0.05) higher in on- pump (3.18±0.31) vs, off-pump (1.60±0.23) [mean ± s.e.]. SHP mRNA was also significantly (p<0.05) higher on-pump (4.58±0.60) vs, off-pump (2.06±0.31) post CABG. FXR and SHP protein paralleled mRNA levels. Post CABG, PGC1α mRNA/protein was not significantly different between on vs. off pump patients. The BAX/BCL2 ratio a measure of apoptosis, was significantly (p<0.05) increased in on-pump (3.50±0.44) vs, off-pump patients (1.44±0.24) post CABG. Of all the possible correlations tested, there was a positive correlation between FXR and BAX/BCL2 ratio (p=0.015, r=0.685) in on-pump patients post CABG. These results suggest that FXR and its target protein SHP are expressed in atrial tissue and are differentially regulated depending on on-pump vs. off-pump CABG. Increased FXR and apoptotic signaling in on-pump CABG vs off-pump CABG and the demonstration of a positive correlation between FXR and the BAX/BCL2 ratio with on-pump CABG, suggests a potential benefit of off-pump CABG. The Farnesoid X receptor (FXR) a member of the nuclear receptor superfamily of ligand-activated transcription factors that functions as an endogenous sensor for bile acids, is expressed mainly in the liver, adipose tissue and intestine. Recent evidence suggests that FXR also acts as a novel functional receptor in murine myocardium, regulating apoptosis and contributing to ischaemia/reperfusion injury. The potential expression and possible function of FXR in the diseased human heart remains largely unknown. The present study aimed to examine the levels of FXR, its ligand proliferator-activated receptor gamma coactivator 1α (PGC1α), its target small heterodimer protein (SHP) at the mRNA and protein levels and parameters of apoptosis (pro-apoptotic BAX/anti-apoptotic BCL2 mRNA ratio) in 59 patients undergoing on- pump CABG and 31 patients off-pump CABG. The on-pump group consisted of 15 women and 44 men with a mean ± S.E. age of 66.57±1.78 and 64.02±1.25 years respectively, and the off- pump patients consisted of 3 women and 28 men with a mean + S.E. age of 69.00±2.08 and 63.46± 1.66 years respectively. We analyzed FXR, SHP, BAX and BCL2 mRNA expression by quantitative Real Time PCR using 18s as an internal control for standardization in right atrial biopsies taken before aortic occlusion and after reperfusion during CABG. FXR and SHP protein was determined by Western blot. FXR mRNA (fold change) post CABG was significantly (p<0.05) higher in on- pump (3.18±0.31) vs, off-pump (1.60±0.23) [mean ± s.e.]. SHP mRNA was also significantly (p<0.05) higher on-pump (4.58±0.60) vs, off-pump (2.06±0.31) post CABG. FXR and SHP protein paralleled mRNA levels. Post CABG, PGC1α mRNA/protein was not significantly different between on vs. off pump patients. The BAX/BCL2 ratio a measure of apoptosis, was significantly (p<0.05) increased in on-pump (3.50±0.44) vs, off-pump patients (1.44±0.24) post CABG. Of all the possible correlations tested, there was a positive correlation between FXR and BAX/BCL2 ratio (p=0.015, r=0.685) in on-pump patients post CABG. These results suggest that FXR and its target protein SHP are expressed in atrial tissue and are differentially regulated depending on on-pump vs. off-pump CABG. Increased FXR and apoptotic signaling in on-pump CABG vs off-pump CABG and the demonstration of a positive correlation between FXR and the BAX/BCL2 ratio with on-pump CABG, suggests a potential benefit of off-pump CABG.