Protein kinase C (PKC) ␤ isoform activity is increased in myocardium of diabetic rodents and heart failure patients. Transgenic mice overexpressing PKC␤2 (PKC␤2Tg) in the myocardium exhibit cardiomyopathy and cardiac fibrosis. In this study, we characterized the expression of connective tissue growth factor (CTGF) and transforming growth factor ␤ (TGF␤) with the development of fibrosis in heart from PKC␤2Tg mice at 4 -16 weeks of age. Heart-to-body weight ratios of transgenic mice increased at 8 and 12 weeks, indicating hypertrophy, and ratios did not differ at 16 weeks. Collagen VI and fibronectin mRNA expression increased in PKC␤2Tg hearts at 4 -12 weeks. Histological examination revealed myocyte hypertrophy and fibrosis in 4-to 16-week PKC␤2Tg hearts. CTGF expression increased in PKC␤2Tg hearts at all ages, whereas TGF␤ increased only at 8 and 12 weeks. In 8-week diabetic mouse heart, CTGF and TGF␤ expression increased two-and fourfold, respectively. Similarly, CTGF expression increased in rat hearts at 2-8 weeks of diabetes. This is the first report of increased CTGF expression in myocardium of diabetic rodents suggesting that cardiac injury associated with PKC␤2 activation, diabetes, or heart failure is marked by increased CTGF expression. CTGF could act independently or together with other cytokines to induce cardiac fibrosis and dysfunction. Diabetes 51:2709 -2718, 2002 C ardiomyopathy associated with diabetes can occur regardless of coronary artery disease and is characterized by myocyte hypertrophy and fibrosis (1,2). Ventricles from diabetic patients show accumulation of PAS-positive glycoproteins, collagen, and active fibroblasts (2). Similarly, ventricle from diabetic rodents show increased fibrosis and expression of the extracellular matrix (ECM) components fibronectin, collagen IV, and collagen VI (3-5). Ventricular remodeling along with changes such as defective calcium transport or fatty acid metabolism can impair contractility. Animals and patients with diabetes show reduced stroke volume and increased end-diastolic pressure (6 -9), which collectively could precipitate heart failure.Activation of the protein kinase C (PKC)/diacylglycerol (DAG) signaling pathway is one mechanism by which hyperglycemia may exert adverse cardiovascular effects. Inoguchi et al. (10) reported increased membranous PKC activity and total DAG in diabetic rat heart. PKC␤2 isoform was preferentially increased in the membranous fraction of heart and aorta, suggesting that this isoform contributes to diabetic vascular complications. Indeed, administration of the PKC␤ selective inhibitor LY333531 to diabetic rats ameliorated increased glomerular filtration, albumin excretion, and retinal circulation rates (11). Ventricles from patients with end-stage heart failure show increased expression of PKC␤ and increased membranous PKC activity within cardiac myocytes (12). Furthermore, targeted overexpression of PKC␤2 in mouse myocardium resulted in left ventricular hypertrophy, fibrosis, and decreased left ventricular performance, s...

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Conscious Hartley guinea pigs were challenged with LTD4 or LTE4 aerosols. When dynamic compliance (Cdyn) decreased to 50% of its baseline value, the challenge aerosols were stopped and treatment aerosols of salbutamol, the LTD4/E4 antagonist LY171883 Na, atropine, or sodium chloride (control) were begun. After 5 min of continuous exposure to the treatment aerosol, each animal was killed and excised lung gas volume (ELGV) was measured. Salbutamol was equally effective in reversing LTD4- and LTE4-induced Cdyn changes. Aerosolized LY171883 Na was effective against both agonists, but was about threefold more potent against LTE4. In contrast, atropine was very effective in reversing LTD4-induced Cdyn changes, but produced minimal reversal when LTE4 was the challenge agent. Pulmonary gas trapping results supported these observations; ELGV values were closely correlated with 5-min Cdyn measurements for both LTD4 (r = -0.817) and LTE4 (r = -0.831). Thus, although LTD4 and LTE4 are though to act on the same or similar receptors, the pattern of pharmacologic reversal at comparable levels of airway obstruction differs for these two agonists.

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