Khalid AM, Hafstad AD, Larsen TS, Severson DL, Boardman N, Hagve M, Berge RK, Aasum E. Cardioprotective effect of the PPAR ligand tetradecylthioacetic acid in type 2 diabetic mice. Am J Physiol Heart Circ Physiol 300: H2116 -H2122, 2011. First published March 18, 2011 doi:10.1152/ajpheart.00357.2010.-Tetradecylthioacetic acid (TTA) is a novel peroxisome proliferator-activated receptor (PPAR) ligand with marked hypolipidemic and insulin-sensitizing effects in obese models. TTA has recently been shown to attenuate dyslipidemia in patients with type 2 diabetes, corroborating the potential for TTA in antidiabetic therapy. In a recent study on normal mice, we showed that TTA increased myocardial fatty acid (FA) oxidation, which was associated with decreased cardiac efficiency and impaired postischemic functional recovery. The aim of the present study was, therefore, to elucidate the effects of TTA treatment (0.5%, 8 days) on cardiac metabolism and function in a hyperlipidemic type 2 diabetic model. We found that TTA treatment increased myocardial FA oxidation, not only in nondiabetic (db/ϩ) mice but also in diabetic (db/db) mice, despite a clear lipid-lowering effect. Although TTA had deleterious effects in hearts from nondiabetic mice (decreased efficiency and impaired mitochondrial respiratory capacity), these effects were not observed in db/db hearts. In db/db hearts, TTA improved ischemic tolerance, an effect that is most likely related to the antioxidant property of TTA. The present study strongly advocates the need for investigation of the cardiac effects of PPAR ligands used in antidiabetic/hypolipidemic therapy, because of their pleiotropic properties. diabetic cardiomyopathy; cardiac metabolism; ischemia-reperfusion; cardiac function; cardiac efficiency HEART DISEASE IS THE LEADING cause of death in diabetic patients. These patients have greater incidence of acute myocardial infarction (AMI), as well as higher mortality following AMI (17, 36). In addition, asymptomatic diabetic patients are predisposed to heart failure, suggesting a specific cardiomyopathy (13). Although the etiology of diabetic cardiomyopathy is not clear, there is strong evidence for a causal link to altered myocardial metabolism (5, 12).The db/db mouse is a model of type 2 diabetes with cardiomyopathic features, notably reduced mechanical function, and reduced functional recovery following ischemia-reperfusion (3,16,19). In addition, measurements of myocardial substrate utilization show a higher reliance on fatty acid (FA) oxidation for energy production (3), accompanied by reduced cardiac efficiency (8,22). A causal link between altered metabolism, reduced efficiency, and tolerance to ischemia in diabetes is supported by the fact that improving myocardial substrate utilization (inhibition of FA oxidation and stimulation of glucose oxidation), both acutely and following lipid-lowering treatment, can improve cardiac efficiency and postischemic functional recovery in obese/type 2 diabetic models (4, 19, 23).Tetradecylthioacetic acid (TTA) ...