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Published on: December 2, 2014
Caspase inhibition modulates left ventricular remodeling following myocardial infarction through cellular and
William M Yarbrough1, Rupak Mukherjee, Robert E Stroud
1Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Insights
Pharmacologic caspase inhibition (CASPI) reduced left ventricular (LV) remodeling after myocardial infarction (MI) in pigs. CASPI attenuated LV dilation and altered myocyte geometry, suggesting caspases contribute to post-MI remodeling via cellular and extracellular pathways.
Area of Science:
- Cardiovascular Research
- Molecular Medicine
- Translational Science
Background:
- Myocardial infarction (MI) involves myocyte death via necrosis and apoptosis.
- Caspase activation in vitro degrades contractile proteins without inducing apoptosis.
- Caspase activation may drive left ventricular (LV) remodeling post-MI through mechanisms independent of apoptosis.
Purpose of the Study:
- To investigate the effects of pharmacologic caspase inhibition (CASPI) on LV geometry and remodeling in a porcine model of MI.
- To elucidate the role of caspases in cellular and extracellular changes post-MI.
Main Methods:
- A porcine model of MI was created by 60 minutes of coronary artery occlusion followed by reperfusion.
- Pigs were randomized to receive saline or CASPI (IDN6734) post-reperfusion.
- Echocardiography, sonomicrometry, and plasma biomarkers (troponin-I, pro-matrix metalloproteinase-2) were used to assess LV remodeling and myocyte changes over a 7-day follow-up.
Main Results:
- CASPI significantly reduced plasma troponin-I levels compared to saline.
- LV end-diastolic area and interregional length increases were attenuated by 40% and 90% with CASPI, respectively.
- Myocyte length was reduced with CASPI, and plasma-free pro-matrix metalloproteinase-2 increased, indicating reduced conversion to active MMP-2.
Conclusions:
- Pharmacologic caspase inhibition attenuated both regional and global LV remodeling post-MI.
- CASPI altered viable myocyte geometry and modified the in vivo conversion of MMP-2 to its active form.
- Caspase activation post-MI contributes to LV remodeling through both cellular and extracellular mechanisms, involving matrix metalloproteinase (MMP) activity.
Background:
Myocyte death occurs by necrosis and caspase-mediated apoptosis in myocardial infarction (MI). In vitro studies suggest caspase activation causes myocardial contractile protein degradation without inducing apoptosis. Thus, caspase activation may evoke left ventricular (LV) remodeling through independent processes post-MI. The effects of caspase activation on LV geometry post-MI remain unclear. This project applied pharmacologic caspase inhibition (CASPI) to a porcine model of MI.
Methods And Results:
Pigs (34 kg) were instrumented to induce 60 minutes of coronary artery occlusion followed by reperfusion and a 7-day follow-up period. Upon reperfusion, the pigs were randomized to saline (n = 12) or CASPI (n = 10, IDN6734, 6 mg/kg i.v., then 6 mg/kg/h for 24 hours). Plasma troponin-I values were reduced with CASPI compared with saline at 24 hours post-MI (133 +/- 15 vs. 189 +/- 20 ng/mL, respectively, P < 0.05). LV end-diastolic area (echocardiography) and interregional length (sonomicrometry) increased from baseline in both groups but were attenuated with CASPI by 40% and 90%, respectively (P < 0.05). Myocyte length was reduced with CASPI compared with saline (128 +/- 3 vs. 141 +/- 4 microm, respectively, P < 0.05). Plasma-free pro-matrix metalloproteinase-2 values increased from baseline with CASPI (27% +/- 6%, P < 0.05) indicative of reduced conversion to active MMP-2. Separate in vitro studies demonstrated that activated caspase species cleaved pro-MMP-2 yielding active MMP-2 forms and that MMP activity was increased in the presence of activated caspase-3.
Conclusions:
CASPI attenuated regional and global LV remodeling post-MI and altered viable myocyte geometry. Caspases increased MMP activity in vitro, whereas CASPI modified conversion of MMP-2 to the active form in vivo. Taken together, the results of the present study suggest that the elaboration of caspases post-MI likely contribute to LV remodeling through both cellular and extracellular mechanisms.
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