Kallikrein Gene Delivery Improves Serum Glucose and Lipid Profiles and Cardiac Function in Streptozotocin-Induced Diabetic Rats

Abstract

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...

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

“…n=4-6 per group. Asterisks p<0.05 vs SD, section marks p< 0.05 vs STZ + atorvastatin after STZ-injection, as indicated by impaired systolic and diastolic function [33], a finding which is in agreement with others [34][35][36][37]. Atorvastatin treatment in diabetic rats led to a significant improvement of systolic contraction and relaxation compared with untreated diabetic animals (dP/dt max +95%, dP/dt min +64%; p<0.05), whereas atorvastatin did not affect LV function in non-diabetic animals.…”

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

“…This ratio is a marker of increased cardiomyocyte survival probability (Condorelli et al 1999). Furthermore, apo A-I transfer normalised the diabetes-reduced phosphorylation of the pro-survival protein kinase B Akt (Montanari et al 2005;Uchiyama et al 2004) and of its effector eNOS to levels found in non-diabetic hearts ). This finding was further corroborated by experiments in cardiomyocytes.…”

Bradykinine et néphroprotection

“…Un des premiers travaux rapporte la réduction de certains paramètres du stress oxydant par la BK chez le rat diabétique de type 1 [31]. Une réduction de la formation de radical superoxyde et des concentrations sériques en triglycérides et cholestérol a été démon-trée après transfert du gène de la kallicréine [32][33][34]. Inversement, une aggravation du profil du stress oxydant a été décrite chez les souris n'exprimant pas le RB2 [29].…”

“…Bien que l'idée qu'une stimulation du RB2 de la BK puisse induire des effets thérapeutiques bénéfiques reste encore novatrice, ce concept émerge finalements des travaux de plusieurs groupes indépendants [28,29,[32][33][34]. Plusieurs agonistes non peptidiques sont disponibles et ont été testés dans des modèles différents [38][39][40].…”

“…Une autre approche d'activation du SKK repose sur le traitement par injection de gènes codant pour la kallicréine avec comme résultat attendu l'augmentation de la synthèse de BK et donc l'activation du RB2. Le transfert du gène de la kallicréine réduit la glycémie, restaure le profil lipidique et protège la fonction cardiaque chez le rat diabétique de type I [32]. Cette approche montre aussi des effets bénéfiques en améliorant la fibrose rénale chez le rat hypertendu [33,34].…”