We investigated the role of the kallikrein-kinin system in cardiac function and glucose utilization in the streptozotocin (STZ)-induced diabetic rat model using a gene transfer approach. Adenovirus harboring the human tissue kallikrein gene was administered to rats by intravenous injection at 1 week after STZ treatment. Human kallikrein transgene expression was detected in the serum and urine of STZ-induced diabetic rats after gene transfer. Kallikrein gene delivery significantly reduced blood glucose levels and cardiac glycogen accumulation in STZ-induced diabetic rats. Kallikrein gene transfer also significantly attenuated elevated plasma triglyceride and cholesterol levels, food and water intake, and loss of body weight gain, epididymal fat pad, and gastrocnemius muscle weight in STZ-induced diabetic rats. However, these effects were blocked by icatibant, a kinin B2 receptor antagonist. Cardiac function was significantly improved after kallikrein gene transfer as evidenced by increased cardiac output and ؎⌬P/⌬t T issue kallikrein specifically processes low-molecular weight kininogen to produce potent vasoactive kinin peptides (1). Intact kinin binds to the bradykinin B2 receptor and transduces signals through nitric oxide (NO)-cGMP and prostacyclincAMP pathways, thereby modulating a broad spectrum of cellular functions (2). The B2 receptor can be blocked by the specific B2 receptor antagonist icatibant (also known as HOE140) (3). Previous reports have shown that the kallikrein-kinin system (KKS) components are locally expressed in the heart (4), and streptozotocin (STZ)-induced diabetes results in a decrease of active cardiac tissue kallikrein levels (5,6), resulting in increased thickness of the left ventricle wall and cardiac hypertrophy (7). The STZ animal model develops characteristic symptoms of diabetes such as hyperglycemia, hyperlipidemia, and increased water and food intake without body weight gain. In addition, STZ diabetes also induces key symptoms including increased glycogen storage in the myocardium, depressed ventricular performance, and cardiac hypertrophy (8). Our recent studies using gene transfer approaches have demonstrated that the KKS improves cardiac function in animal models of myocardial ischemia, chronic heart failure, and cardiac hypertrophy (9 -11). In addition, transgenic rats overexpressing the human tissue kallikrein gene resulted in reduction of isoproterenol-induced cardiac hypertrophy and fibrosis, and these protective effects were abolished by icatibant (12). These findings indicate a potential protective role of the KKS in diabetic cardiomyopathy.STZ-induced diabetes results in hyperglycemia and hyperlipidemia, and without insulin treatment, animals have poor control over glucose and circulating lipid levels. Previous studies have shown that the KKS is involved in glucose management by stimulating GLUT4 translocation (13), improving insulin stimulation of GLUT4 (14), and preventing dephosphorylation of insulin receptor substrate-1 (15). Whether the KKS plays a role in impro...
improves cardiac function and prevents renal damage in streptozotocin-induced diabetic rats. Am J Physiol Endocrinol Metab 283: E1291-E1298, 2002 10.1152/ajpendo.00147. 2002 is a potent vasodilating peptide and is involved in cardiovascular and renal disease. In the present study, we investigated the role of AM in cardiac and renal function in streptozotocin (STZ)-induced diabetic rats. A single tail-vein injection of adenoviral vectors harboring the human AM gene (Ad.CMV-AM) was administered to the rats 1-wk post-STZ treatment (65 mg/kg iv). Immunoreactive human AM was detected in the plasma and urine of STZ-diabetic rats treated with Ad.CMV-AM. Morphological and chemical examination showed that AM gene delivery significantly reduced glycogen accumulation within the hearts of STZ-diabetic rats. AM gene delivery improved cardiac function compared with STZ-diabetic rats injected with control virus, as observed by decreased left ventricular enddiastolic pressure, increased cardiac output, cardiac index, and heart rate. AM gene transfer significantly increased left ventricular long axis (11.69 Ϯ 0.46 vs. 10.31 Ϯ 0.70 mm, n ϭ 10, P Ͻ 0.05) and rate of pressure rise and fall (ϩ6,090.1 Ϯ 597.3 vs. ϩ4,648.5 Ϯ 807.1 mmHg/s), (Ϫ4,902.6 Ϯ 644.2 vs. Ϫ3,915.5 Ϯ 805.8 mmHg/s, n ϭ 11, P Ͻ 0.05). AM also significantly attenuated renal glycogen accumulation and tubular damage in STZ-diabetic rats as well as increased urinary cAMP and cGMP levels, along with increased cardiac cAMP and Akt phosphorylation. We also observed that delivery of the AM gene caused an increase in body weight along with phospho-Akt and membrane-bound GLUT4 levels in skeletal muscle. These results suggest that AM plays a protective role in hyperglycemia-induced glycogen accumulation and cardiac and renal dysfunction via Akt signal transduction pathways.
Serum lipoproteins were studied in active and sedentary young women. The groups were matched for age, body weight, and blood pressure. A quantitative and qualitative evaluation of the diet was performed. In spite of a higher intake of saturated fat and cholesterol, serum concentrations of triglyceride, total cholesterol, and low-density lipoprotein cholesterol in the active group were not significantly different from the controls. Nevertheless, high-density lipoprotein cholesterol (HDL-C) levels were significantly higher in the active subjects even after covariance adjustment for nutrient intake; therefore, the HDL-C increase seems to depend on physical activity "per se" rather than on differences in diet.
P58 The tissue kallikrein-kinin system is locally present in the heart and is reduced under diabetic conditions. In the present study, we explored the effects of kallikrein gene delivery in the heart under diabetic conditions. Intravenous injection of streptozotocin (STZ) (60mg/kg) into 8-week-old male Sprague-Dawley rats produced hyperglycemia (460 ± 10 mg/dl, n=30). Three weeks after STZ treatment, adenovirus containing the human tissue kallikrein gene (Ad.CMV-cHK) or green fluorescence protein gene (Ad.CMV-GFP) under the control of CMV promoter/enhancer were injected via the tail vein into STZ-diabetic rats. Adenovirus-mediated kallikrein gene delivery caused a significant reduction of blood pressure as compared to control rats receiving control virus (170.8 ± 3.5 vs. 187.4 ± 4.2 mmHg, n=8, P<0.01). Rats were sacrificed and tissues were collected for analysis at 16 days after gene delivery. Histological examination of heart sections stained with periodic acid-Schiff (PAS) showed marked accumulation of glycogen in cardiomyocytes of diabetic rats. Kallikrein gene delivery significantly reduced cardiac glycogen accumulation as compared to rats receiving control adenovirus. Quantitative analysis confirmed the morphological observation that kallikrein gene delivery significantly reduced cardiac glycogen levels as compared to control diabetic rats injected withAd.CMV-GFP (0.5 ± 0.07 vs. 2.15 ± 0.83 mg glycogen/mg protein, n=6, P<0.05). Cardiac cAMP levels were significantly increased after kallikrein gene delivery. This is the first study to demonstrate that kallikrein gene delivery exerts a protective effect in the reduction of glycogen accumulation in cardiomyocytes of STZ-induced diabetic rats.
P201 Our recent studies showed that adenovirus-mediated human tissue kallikrein gene delivery attenuated hypertension, cardiac hypertrophy, and renal injury in various hypertensive rat models. However, mechanisms underlying the beneficial effects of human kallikrein gene delivery are not clear. In the present study, we investigated the potential of human kallikrein gene delivery on synthesis and excretion of endogenous rat tissue kallikrein in normotensive and hypertensive rat models. Adenovirus carrying the human kallikrein cDNA under the control of cytomegalovirus (CMV) promoter/enhancer was administered via tail vein injection. Control rats received adenovirus harboring the b-galactosidase or luciferase gene under control of the CMV promoter/enhancer. A single injection of the human tissue kallikrein gene caused a prolonged blood pressure-lowering effect in spontaneously hypertensive rats, two kidney-one clip, Dahl salt-sensitive, deoxycorticosterone acetate-salt and monocrotaline-induced pulmonary hypertensive rats, while systolic blood pressure of normotensive Sprague-Dawley rats remained unaltered. Human kallikrein gene delivery significantly increased endogenous rat tissue kallikrein levels in the kidney and urine of different models of hypertensive rats as compared with their respective controls. However, urinary excretion of rat tissue kallikrein was not affected by human kallikrein gene delivery in normotensive rats. The endogenous rat tissue kallikrein mRNA expression in the kidney remained unaltered after human kallikrein gene delivery, which indicated that expression of human kallikrein in hypertensive rats increased endogenous rat kallikrein synthesis and excretion. These findings indicate that beneficial effects of human kallikrein gene delivery in hypertensive rat models are mediated, at least in part, by enhanced endogenous tissue kallikrein-kinin system.
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