ABSTRACT
Title
Cardioprotective and anti-apoptotic effects of heme oxygenase-1 in post-ischemic remodelling
Authors
R. Mastroianni1, C. Lanzi1, M. Fazi2, N. Mugelli1, M. Collino3, D. Bani4, A. Pini1 and E. Masini1.
Departments of1Preclinical and Clinical Pharmacology, 2Critical Medical and Surgical Care and 4Anatomy, Histology and Forensic Medicine, Section of Histology, University of Florence, 50139 Florence,3Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy.
Departments of1Preclinical and Clinical Pharmacology, 2Critical Medical and Surgical Care and 4Anatomy, Histology and Forensic Medicine, Section of Histology, University of Florence, 50139 Florence,3Anatomy, Pharmacology and Forensic Medicine, University of Turin, Turin, Italy.
Abstract
Heme oxygenase-1 (HO-1) is a rapidly inducible cytoprotective protein that degrades heme to biliverdin, ferrous iron and carbon monoxide (CO). HO-1 is endowed with antioxidant, antiapoptotic, and anti-inflammatory effects and mitigates cellular injury. However its pathophysiological role in cardiac remodeling is unknown. We hypothesized that induction of HO-1 in ischemic heart reduces pathological cellular damage and pathological remodeling.
Sprague-Dawley male rats underwent either sham operation or permanent left anterior descending coronary artery ligation to induce cardiac ischemia. The rats were treated with hemin (4 mg/Kg b.w. i.p. every 48 hours for 4 weeks) starting the same day of the operation. Rat echocardiography was performed and analyzed at baseline and 4 weeks postoperatively.
Blood was sampled was withdrawn at the same time for blood CO and plasma TNFα, IL1β and IL10 determination. Ischemic area was determined in a subset of animals with the use of nitrobluetetrazolium chloride (NBT) assay. Cardiac samples from sham-operated, ischemic heart treated or not with hemin were used for the evaluation of HO-1 expression and activity, malonyldialdehyde (MDA) and 8-OH-d-guanosine levels, myeloperoxidase (MPO) and caspase-3 activity.
Four weeks after ligation, the rats treated with hemin exhibited a significant reduction of necrotic area associated with a reduction of the markers of inflammation, oxidative stress and apoptosis and of ventricular remodeling. Moreover, a significant decrease of TNFα and IL1β and a significant increase of IL10 plasma level in hemin-treated animals was observed. HO-1 expression and HO-1-derived CO was increased in cardiac samples and in blood of ischemic and hemin-treated rats.
HO-1 induction in the ischemic heart is an important cardioprotective enzyme that counteracts pathological left ventricular remodeling. This effect is at least in part mediated by a CO-dependent modulation of cytokine production.
This research was supported by grants of ECRF, PRIN and INRC.
Sprague-Dawley male rats underwent either sham operation or permanent left anterior descending coronary artery ligation to induce cardiac ischemia. The rats were treated with hemin (4 mg/Kg b.w. i.p. every 48 hours for 4 weeks) starting the same day of the operation. Rat echocardiography was performed and analyzed at baseline and 4 weeks postoperatively.
Blood was sampled was withdrawn at the same time for blood CO and plasma TNFα, IL1β and IL10 determination. Ischemic area was determined in a subset of animals with the use of nitrobluetetrazolium chloride (NBT) assay. Cardiac samples from sham-operated, ischemic heart treated or not with hemin were used for the evaluation of HO-1 expression and activity, malonyldialdehyde (MDA) and 8-OH-d-guanosine levels, myeloperoxidase (MPO) and caspase-3 activity.
Four weeks after ligation, the rats treated with hemin exhibited a significant reduction of necrotic area associated with a reduction of the markers of inflammation, oxidative stress and apoptosis and of ventricular remodeling. Moreover, a significant decrease of TNFα and IL1β and a significant increase of IL10 plasma level in hemin-treated animals was observed. HO-1 expression and HO-1-derived CO was increased in cardiac samples and in blood of ischemic and hemin-treated rats.
HO-1 induction in the ischemic heart is an important cardioprotective enzyme that counteracts pathological left ventricular remodeling. This effect is at least in part mediated by a CO-dependent modulation of cytokine production.
This research was supported by grants of ECRF, PRIN and INRC.