Abstract 12934: Potentiation of Aspirin Induced Amelioration of Cardiovascular Dysfunction in Diabetic Rats by Minocycline
Interruptions of Matrix Metalloproteinase-2 (MMP-2) and Matrix Metalloproteinase-9 (MMP-9) have been shown to reduce the ensuing threatening risk factors of cardiovascular complications of diabetes by alteration in Extracellular Matrix. We hypothesized that minocycline induced MMP-2 and MMP-9 inhibition can be enhanced by aspirin (through its COX and tPA inhibitory action) and this combination can reduce cardiovascular dysfunction of diabetes. Three weeks after diabetes induction (Streptozotocin, 55 mg/kg i.p.), rats were treated with minocycline (50 mg/kg, p.o.), aspirin (50 mg/kg, p.o.), or minocycline (50 mg/kg, p.o.) plus aspirin (50 mg/kg, p.o.) for a period of three weeks. At the end of sixth week, arterial pressure, heart rate and left ventricular pressure were recorded. Contractile response to phenylephrine (10−5 M) and relaxation responses to acetylcholine (10−9 to 10−4 M) were obtained from aortic rings of diabetic rats. Cardiac hypertrophy was measured and histopathology was done using Masson's Trichrome stain method. Collagen level was estimated by image analysis. Gel zymography was performed to evaluate MMP-2 and MMP-9 levels. Heart rate, mean arterial pressure, + dp/dtmax and -dp/dtmax were found significantly decreased in STZ diabetic rats (279 ± 16, 107 ± 8 mmHg, 4533 ± 345 and −3162 ± 259 mmHg/s respectively) when compared with normoglycemic group (218 ± 23, 79 ± 7mmHg, 2537 ± 364 and −2183 ± 274 mmHg/s respectively). Treatment with combination of minocycline and aspirin significantly ameliorated these parameters (243 ± 27, 98 ± 9, 4187 ± 421 and − 2861 ± 269 mmHg/s respectively) compared to vehicle treated diabetic group. Endothelium-dependent relaxation responses induced by acetylcholine were decreased in diabetic rats (% relaxation 59.64 ± 2.99) and significantly higher in combination treated group (% relaxation 27.84 ± 2.537). Collagen, MMP-2 and MMP-9 levels were significantly decreased in combined treated group when compared with diabetic controls. Present study revealed that minocycline potentiated aspirin induced attenuation of cardiovascular dysfunction in diabetic rats by enhanced MMP-2&MMP-9 inhibition and can be a potential approach for the treatment.
- © 2010 by American Heart Association, Inc.