Seropian I.M.,Pauley Heart Center |
Seropian I.M.,Victoria Johnson Center |
Seropian I.M.,Virginia Commonwealth University |
Abbate A.,Pauley Heart Center |
And 12 more authors.
Journal of Cardiovascular Pharmacology
Background: Phosphoinositide 3-kinase gamma is upregulated in the heart during acute myocardial infarction (AMI) potentially contributing to the development and maintenance of heart failure. Methods: CD-1 male mice were randomly assigned to pharmacologic inhibition of phosphoinositide 3-kinase gamma using AS- 605240 (10 mg/kg/day intraperitoneally) or vehicle (NaCl 0.9% + DMSO 25% solution) for 14 days after experimental AMI induced by surgical coronary artery ligation. Echocardiography was performed at baseline and 1, 7, 14, and 28 days after surgery to measure left ventricular dimensions and function. Infarct size was also measured at weekly intervals to evaluate for infarct resorption. Results: When compared with vehicle-treated mice over the 4-week period, animals treated with AS-605240 showed a smaller increase in left ventricular cavitary dimensions, a smaller decrease in left ventricular systolic function (P < 0.05), and a significant increase in posterior wall diastolic and systolic thickness reflective of compensatory hypertrophy (P < 0.05). Initial infarct size (measured at 24 hours) was not different comparing AS-605240 (29% ± 4%) and vehicle-treated mice (31% ± 1%, P = nonsignificant). At 4 weeks after AMI, infarct size was significantly smaller in the AS-605240- treated mice (14%± 2%) compared with vehicle-treated mice (28% ± 3%, P , 0.001), reflecting greater infarct resorption. Conclusions: Phosphoinositide 3-kinase gamma inhibition with AS-605240 after AMI leads to enhanced infarct resorption, greater compensatory hypertrophy of the nonischemic myocardium, and more favorable cardiac remodeling and function. Copyright © 2010 by Lippincott Williams & Wilkins. Source
Mezzaroma E.,Virginia Commonwealth University |
Mezzaroma E.,Victoria Johnson Center |
Mikkelsen R.B.,Massey Cancer Center |
Toldo S.,Virginia Commonwealth University |
And 12 more authors.
Thoracic X-ray therapy (XRT), used in cancer treatment, is associated with increased risk of heart failure. XRT-mediated injury to the heart induces an inflammatory response leading to cardio myopathy. The aim of this study was to determine the role of interleukin (IL)-1 in response to XRT injury to the heart and on the cardio myopathy development in the mouse. Female mice with genetic deletion of the IL-1 receptor type I (IL-1R1 knockout mice [IL-1R1 KO]) and treatment with recombinant human IL-1 receptor antagonist anakinra, 10 mg/kg twice daily for 7 d, were used as independent approaches to determine the role of IL-1. Wild-type (wt) or IL-1R1 KO mice were treated with a single session of XRT (20 or 14 gray [Gy]). Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson’s trichrome was used to assess myocardial fibrosis and pericardial thickening. After 20 Gy, the contractile reserve was impaired in wt mice at d 3, and the LV ejection fraction (EF) was reduced after 4 months when compared with sham-XRT. IL- 1R1 KO mice had preserved contractile reserve at 3 d and 4 months and LVEF at 4 months after XRT. Anakinra treatment for 1 d before and 7 d after XRT prevented the impairment in contractile reserve. A significant increase in LV end-diastolic pressure, associated with increased myocardial interstitial fibrosis and pericardial thickening, was observed in wt mice, as well as in IL-1R1 KO- or anakinra-treated mice. In conclusion, induction of IL-1 by XRT mediates the development of some, such as the contractile impairment, but not all aspects of the XRT-induced cardiomyopathy, such as myocardial fibrosis or pericardial thickening. © 2015, Uninversity of Michigan. All rights reserved. Source