Protective role of Kalpaamruthaa in type II diabetes mellitus-induced cardiovascular disease through the modulation of protease-activated receptor-1.

BACKGROUND: Kalpaamruthaa (KA) is a formulatory herbal preparation has beneficial antioxidant, anti-apoptotic and anti-inflammatory properties against cardiovascular damage (CVD). OBJECTIVE: The present study was undertaken to investigate the protective role of KA in type II diabetes mellitus-induced CVD through the modulation of protease-activated receptor-1 (PAR1). MATERIALS AND METHODS: CVD was developed in 8 weeks after type II diabetes mellitus induction with high fat diet (2 weeks) and low dose of streptozotocin (2 × 35 mg/kg b.w. i.p. in 24 h interval). CVD-induced rats treated with KA (200 mg/kg b.w. in 0.5 ml of olive oil) orally for 4 weeks. RESULTS: KA increased the activities of enzymatic antioxidants and the levels of non-enzymatic antioxidants in pancreas of CVD-induced rats. KA effectively reduced the lipid peroxides and carbonyl content in the pancreas of CVD-induced rats. KA reduced cellular damage by ameliorating the activities of marker enzymes in plasma, heart and liver. The protective nature of KA was further evidenced by histological observation in pancreas. Further, KA reduced CVD by decreasing the expression of PAR1 in heart. CONCLUSION: This study exhibits the defending role of KA in type II diabetes mellitus-induced CVD through altering PAR1.

Kalpaamruthaa ameliorates mitochondrial and metabolic alterations in diabetes mellitus induced cardiovascular damage.

Efficacy of Kalpaamruthaa on the activities of lipid and carbohydrate metabolic enzymes, electron transport chain complexes and mitochondrial ATPases were studied in heart and liver of experimental rats. Cardiovascular damage (CVD) was developed in 8 weeks after type 2 diabetes mellitus induction with high fat diet (2 weeks) and low dose of streptozotocin (2 × 35 mg/kg b.w. i.p. in 24 hr interval). In CVD-induced rats, the activities of total lipase, cholesterol ester hydrolase and cholesterol ester synthetase were increased, while lipoprotein lipase and lecithin-cholesterol acyltransferase activities were decreased. The activities of lipid-metabolizing enzymes were altered by Kalpaamruthaa in CVD-induced rats towards normal. Kalpaamruthaa modulated the activities of glycolytic enzymes (hexokinase, phosphogluco-isomerase, aldolase and glucose-6-phosphate dehydrogenase), gluconeogenic enzymes (glucose-6-phosphatase and fructose-1, 6-bisphosphatase) and glycogenolytic enzyme (glycogen phosphorylase) along with increased glycogen content in the liver of CVD-induced rats. The activities of isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, α-ketoglutarate dehydrogenase, Complexes and ATPases (Na(+)/K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase) were decreased in CVD-induced rats, which were ameliorated by the treatment with Kalpaamruthaa. This study ascertained the efficacy of Kalpaamruthaa for the treatment of CVD in diabetes through the modulation of metabolizing enzymes and mitochondrial dysfunction.

Kalpaamruthaa modulates oxidative stress in cardiovascular complication associated with type 2 diabetes mellitus through PKC-ß/Akt signaling.

This study aimed at investigating the efficacy of Kalpaamruthaa (KA) on cardiovascular damage (CVD) associated with type 2 diabetes mellitus in experimental rats by reducing oxidative stress and the modulation of the protein kinase C-ß (PKC-ß)/Akt signaling pathway. CVD-induced rats were treated with KA (200 mg·(kg body mass)(-1)·(day)(-1)) orally for 4 weeks. KA effectively reduced insulin resistance with alterations in blood glucose, hemoglobin, and glycosylated hemoglobin in CVD-induced rats. Elevated levels of lipids in CVD-induced rats were decreased upon KA administration. In CVD-induced rats the levels of lipoproteins were returned to normal by KA treatment. KA effectively reduced the lipid peroxidative product and protein carbonyl content in liver of CVD-induced rats. KA increased the activities and (or) levels of enzymatic and nonenzymatic antioxidants in liver of CVD-induced rats. KA treatment reduced the fatty inclusion and mast cell infiltration in liver of CVD-induced rats. Further, treatment with KA reduced the chromatin condensation and marginization in myocardium of CVD-induced rats. KA alters insulin signaling by decreasing PKC-ß and increasing p-Akt and GLUT4 expressions in heart of CVD-induced rats. The above findings suggest that KA renders protection against CVD induced by type 2 diabetes mellitus by augmenting the cellular antioxidant defense capacity and modulating PKC-ß and the p-Akt signaling pathway.

Kalpaamruthaa ameliorates myocardial and aortic damage in cardiovascular complications associated with type 2 diabetes mellitus.

Myocardial and aortic damage in cardiovascular complications (CVD) associated with type 2 diabetes mellitus and the protective efficacy of Kalpaamruthaa (KA) are evaluated in this study. CVD developed in 8 weeks after type 2 diabetes mellitus was induced by the administration of a high-fat diet for 2 weeks, and then with streptozotocin (2 × 35 mg·(kg body mass)(-1), by intraperitonal injection, at 24 h intervals) in male Sprague-Dawley rats. CVD-induced rats were treated with KA at 200 mg·(kg body mass)(-1)·(day)(-1) orally for 28 days. Increased oxidative stress in CVD-induced rats lowers antioxidant defense in the aorta. Treatment with KA reduced oxidative stress by increasing antioxidant status with decreased lipid peroxides in CVD-induced rats. Histological examination of the myocardium and aorta provided support for the cytoprotective effect of KA in CVD. Ultrastructural changes in the myocardium of CVD-induced rats were improved by KA treatment. Aortic damage was observed through decreased endothelial nitric oxide synthase and increased NADPH oxidase mRNA expressions in CVD-induced rats. KA reduced the aortic damage by ameliorating these levels back to normal. KA treatment reduced the pro-inflammatory cytokines tumor necrosis factor-α and interleukin 6 in CVD-induced rats. Immunohistochemical expressions of matrix metalloproteinase-2 and -9 were observed to be elevated in the myocardium of CVD-induced rats, but these were decreased by the administration of KA. This study demonstrates the cardiovascular protective effect of KA in type 2 diabetes.

Complete vascular healing and sustained suppression of neointimal thickening after local delivery of advanced c-myc antisense at six months follow-up in a rabbit balloon injury model.

BACKGROUND: Neointimal hyperplasia following percutaneous transluminal coronary angioplasty (PTCA) is one of the major components of the process of restenosis. We evaluated the long-term impact of local delivery of c-myc neutrally charged antisense oligonucleotides (Resten-NG) upon neointimal formation following PTCA in a rabbit model. METHODS: PTCA was performed in the iliac arteries of 10 New Zealand white rabbits at 8 atm for 30 s, three times. An infusion of 500 micro g Resten-NG (n=6) or saline (n=4) was delivered to the site at 2 atm via the outer balloon pores of the transport catheter over 2 min. The diet was supplemented with 0.25% cholesterol for 10 days before and 6 months following PTCA. RESULTS: After 6 months, animals were sacrificed and vessels were fixed in formalin, processed and stained with hematoxylin, eosin, and movat. Histological analysis revealed complete vascular healing in both groups of animals. Planimetry showed that intimal areas were 1.71+/-0.25 and 0.65+/-0.36 mm2 in the control and antisense delivery groups, respectively (P<.05). CONCLUSION: We conclude that local delivery of Resten-NG significantly inhibited neointimal thickening following PTCA in a rabbit for up to 6 months.