Clofibrate, a Unique Fibrate that Augments Cardiac Contractility Through a PPARa‐independent Mechanism

Background Fibrates are a group of synthetic peroxisomal proliferator‐activated receptor alpha (PPARα) agonists that have been in clinical use for several decades for their hypolipidemic properties. Clofibrate is the pioneer drug in the class of fibrates which have been shown to reduce triglyceride levels and elevate HDL cholesterol levels through PPARα agonism. More recently, non‐genomic actions of fibrates have received attention. In our previous experiments, we have demonstrated that fibrates induced acute relaxation of mouse aorta through non‐PPARα mediated mechanisms. Clofibrate, in particular, has been shown to inhibit Na+/K+ ATPase (NKA) activity in the rat kidney. It is well known that the NKA pump also plays an important role in maintaining calcium homeostasis in cardiomyocytes and NKA pump inhibition results in increased cardiac contractility. However, the direct effects of fibrates on cardiac muscle have not been tested. The objective of this study was to determine if clofibrate alters cardiac contractility independent of stimulation of PPARa. Methods Left ventricular muscle strips were isolated from 12–16 week‐old male wild type (WT) and PPARa null mice at 1 Hz in an oxygenated organ bath. Contractile waveforms were analyzed after treatment with clofibrate, clofibrate ester, gemfibrozil, and Wyeth 14,643 and also compared to the well‐known NKA pump inhibitor ouabain. Results We found that the effect of clofibrate on cardiac contractility in WT mice was concentration‐dependent with a 1.3 and 1.5‐fold increase above baseline at 2 and 20 μM concentrations, respectively (n= 7; P<0.05) and with no significant increase at 0.2 mM (P>0.05). The contractile response to clofibrate in PPARα deficient muscle strips was similar to WT with significant increases at 2 and 20 mM (n=7; P<0.05). Clofibrate ester, gemfibrozil and Wyeth 14,643, did not increase cardiac contractility (n=4; P>0.05). The change in contractile force of the muscle strips after administration of clofibrate was comparable to ouabain in WT mice (n=5; P<0.05). Conclusions Our findings show that clofibrate uniquely augments cardiac contractility through a PPARα‐independent mechanism which was comparable to the effect produced by the NKA pump inhibitor ouabain. Based on these results, there may be a new mechanism of action for clofibrate in cardiac contractility and could be explored as a novel heart failure treatment strategy.