Three forms of PPARs are expressed in the heart. In animal models, PPARγ agonist treatment improves lipotoxic cardiomyopathy; however, PPARγ agonist treatment of humans is associated with peripheral edema and increased heart failure. To directly assess effects of increased PPARγ on heart function, we created transgenic mice expressing PPARγ1 in the heart via the cardiac α-myosin heavy chain (α-MHC) promoter. PPARγ1-transgenic mice had increased cardiac expression of fatty acid oxidation genes and increased lipoprotein triglyceride (TG) uptake. Unlike in cardiac PPARα-transgenic mice, heart glucose transporter 4 (GLUT4) mRNA expression and glucose uptake were not decreased. PPARγ1-transgenic mice developed a dilated cardiomyopathy associated with increased lipid and glycogen stores, distorted architecture of the mitochondrial inner matrix, and disrupted cristae. Thus, while PPARγ agonists appear to have multiple beneficial effects, their direct actions on the myocardium have the potential to lead to deterioration in heart function.

Intracellular lipid accumulation in the heart is associated with cardiomyopathy, yet the precise role of triglyceride (TG) remains unclear. With exercise, wild type hearts develop physiologic hypertrophy. This was associated with greater TG stores and a marked induction of the TG-synthesizing enzyme diacylglycerol (DAG) acyltransferase 1 (DGAT1). Transgenic overexpression of DGAT1 in the heart using the cardiomyocytespecific ␣-myosin heavy chain (MHC) promoter led to approximately a doubling of DGAT activity and TG content and reductions of ϳ35% in cardiac ceramide, 26% in DAG, and 20% in free fatty acid levels. Cardiac function assessed by echocardiography and cardiac catheterization was unaffected. These mice were then crossed with animals expressing long-chain acyl-CoA synthetase via the MHC promoter (MHC-ACS), which develop lipotoxic cardiomyopathy. MHC-DGAT1XMHC-ACS double transgenic male mice had improved heart function; fractional shortening increased by 74%, and diastolic function improved compared with MHC-ACS mice. The improvement of heart function correlated with a reduction in cardiac DAG and ceramide and reduced cardiomyocyte apoptosis but increased fatty acid oxidation. In addition, the survival of the mice was improved. Our study indicates that TG is not likely to be a toxic lipid species directly, but rather it is a feature of physiologic hypertrophy and may serve a cytoprotective role in lipid overload states. Moreover, induction of DGAT1 could be beneficial in the setting of excess heart accumulation of toxic lipids.Triglyceride (TG) 2 is the major energy storage form in organs. The final step of TG synthesis, the conversion of diacylglycerol (DAG) to TG, is catalyzed by diacylglycerol acyltransferase (DGAT) enzymes. DGAT1 and DGAT2 are unrelated proteins that exhibit DGAT activity (1). DGAT1 belongs to a gene family that includes ACAT1 and ACAT2 (acyl-CoA:cholesterol acyltransferases 1 and 2) (1-3), whereas DGAT2 is a member of a larger gene family whose members include acylCoA:monoacylglycerol acyltransferase (3). Although both enzymes catalyze the same reaction in TG synthesis, they are functionally distinguished by their differences in regulation and substrate specificity (2, 4 -7). For example, DGAT1, but not DGAT2, will esterify other lipids such as retinol (2,8). DGAT1 is widely expressed in all tissues, with high expression in white adipose tissue, skeletal muscle, heart, and intestine (1); DGAT2 is primarily expressed in the liver (1, 2).Studies to understand the roles of DGAT1 and -2 have been performed using genetically modified mice. Investigators have studied whether DGATs regulate insulin actions and toxic effects of lipids on tissue. DGAT1 knock-out mice have reduced obesity on a high fat diet (6). Moreover, when these mice were crossed onto the agouti background they had increased insulin sensitivity (9). Transplantation of DGAT1-deficient adipose tissue into wild type (WT) mice decreased adiposity and increased insulin sensitivity (10). These experiments suggest that DGAT1 inhi...

No abstract

Genetic modifications that affect lipid uptake, oxidation, and storage are being exploited to elucidate the pathophysiology of cardiomyopathies and to discover how lipids relate to heart failure in humans with obesity and diabetes mellitus. This information is likely to lead to new diagnostic categories of cardiomyopathy and more pathophysiologically appropriate treatments.

The present study was undertaken to determine the effects of interleukin-1 beta (IL-1 beta) on renal sympathetic nerve activity (RSNA), arterial blood pressure (AP), heart rate (HR), and body temperature in conscious rats. Either intravenous or intracerebroventricular administration of IL-1 beta elicited increases in AP, HR, and RSNA accompanied by a rise in body temperature. The maximum changes in AP, HR, and RSNA occurred 10-15 min after intravenous injection of IL-1 beta (100 ng) and 20-25 min after intracerebroventricular injection (5 ng). The responses induced by the intravenous and intracerebroventricular injections lasted for approximately 15-30 min and did not appear when the animals were pretreated with the cyclooxygenase inhibitor indomethacin (10 mg/kg iv). Moreover, intracerebroventricular injection of prostaglandin E2 (1 microgram) produced responses similar to those induced by IL-1 but with shorter latency. Plasma norepinephrine and adrenocorticotropic hormone concentrations were increased after IL-1 beta injection. The results suggested that IL-1 beta augments cardiovascular and sympathetic outflow through the central action of prostaglandin E2 in conscious rats.