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Gö 6983 exerts cardioprotective effects in myocardial ischemia/reperfusion
Ellen E Peterman1, Philip Taormina, Margaret Harvey
1Department of Pathology, Philadelphia College of Osteopathic Medicine Philadelphia, Pennsylvania 19131-1694, USA.
Abstract:
Ischemia followed by reperfusion (I/R) in the presence of polymorphonuclear leukocytes (PMNs) results in cardiac contractile dysfunction. Inhibiting protein kinase C (PKC) inhibits the release of superoxide from PMNs. The compound Gö 6983 is an inhibitor of all five PKC isoforms present in PMNs. Therefore, we hypothesized that Gö 6983 could attenuate PMN-induced cardiac dysfunction by suppression of superoxide production from PMNs. We studied isolated rat hearts following ischemia (20 minutes) and reperfusion (45 minutes) infused with activated PMNs. In hearts reperfused with PMNs and Gö 6983 (100 nM, n = 7), left ventricular developed pressure (LVDP) and the rate of LVDP (+dP/dt max) recovered to 89 +/- 7% and 74 +/- 2% of baseline values, respectively, at 45 minutes postreperfusion compared with I/R hearts (n = 9) receiving PMNs alone, which only recovered to 55 +/- 3% and 45 +/- 5% of baseline values for LVDP and +dP/dtmax, respectively (P < 0.01). Gö 6983 (100 nM) significantly reduced PMN adherence to the endothelium and infiltration into the myocardium compared with I/R + PMN hearts (P < 0.01), and significantly inhibited superoxide release from PMNs by 90 +/- 2% (P < 0.01). In the presence of PMNs, Gö 6983 attenuated post-I/R cardiac contractile dysfunction, which may be related in part to decreased superoxide production.
Insights
Gö 6983, a protein kinase C (PKC) inhibitor, significantly improved cardiac function after ischemia-reperfusion injury by reducing superoxide production from polymorphonuclear leukocytes (PMNs). This compound attenuated PMN-induced cardiac dysfunction.
Area of Science:
- Cardiovascular Science
- Immunology
- Pharmacology
Background:
- Ischemia-reperfusion (I/R) injury in the heart is exacerbated by polymorphonuclear leukocytes (PMNs).
- PMN-derived superoxide contributes to cardiac contractile dysfunction during I/R.
- Protein kinase C (PKC) regulates PMN superoxide release.
Purpose of the Study:
- To investigate the potential of Gö 6983, a PKC inhibitor, in mitigating PMN-induced cardiac dysfunction following I/R.
- To determine if Gö 6983 attenuates cardiac dysfunction by suppressing PMN superoxide production.
Main Methods:
- Isolated rat hearts underwent 20 minutes of ischemia followed by 45 minutes of reperfusion.
- Hearts were infused with activated PMNs, with or without Gö 6983 (100 nM).
- Cardiac function (left ventricular developed pressure, +dP/dt max), PMN adherence, infiltration, and superoxide release were measured.
Main Results:
- Gö 6983 treatment significantly improved recovery of left ventricular developed pressure and +dP/dt max compared to controls (89% vs 55% and 74% vs 45%, respectively).
- Gö 6983 significantly reduced PMN adherence and myocardial infiltration.
- Gö 6983 inhibited PMN superoxide release by 90%.
Conclusions:
- Gö 6983 effectively attenuates post-ischemia-reperfusion cardiac contractile dysfunction in the presence of PMNs.
- The cardioprotective effects of Gö 6983 may be partly mediated by the suppression of PMN superoxide production.
