Author: Mingoia, Joseph T. ; Spinale, Francis G. ; Hendrick, Jennifer W. ; Mukherjee, Rupak ; Stroud, Robert E. ; Yarbrough, William M. ; Meyer, Evan C. ; Sample, Jeffrey A. ; Escobar, G. Patricia

BACKGROUNDMyocyte 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 RESULTSPigs (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.CONCLUSIONSCASPI 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.

01 Dec 2003·The Journal of Thoracic and Cardiovascular SurgeryQ1 · MEDICINE

Pharmacologic inhibition of intracellular caspases after myocardial infarction attenuates left ventricular remodeling: a potentially novel pathway

Q1 · MEDICINE

Article

Author: William C Gibson ; Fred A Crawford ; Patrick C White ; William M Yarbrough ; G.Patricia Escobar ; Francis G Spinale ; Robert C Armstrong ; Rupak Mukherjee ; Amy E Hardin ; Kathryn B Dowdy ; Jennifer W Hendrick ; Ann Stiko ; Joseph T Mingoia ; Jeffrey A Sample ; Julie E McLean

OBJECTIVEMyocyte death occurs by necrosis and caspase-mediated apoptosis in the setting of myocardial infarction. In vitro studies suggest that caspase activation within myocytes causes contractile protein degradation without inducing cell death. Thus, caspase activation may evoke left ventricular remodeling through 2 independent processes post-myocardial infarction. However, the effects of caspase activation on left ventricular geometry post-myocardial infarction remain unclear. This project applied broad-spectrum caspase inhibition to a chronic porcine model of myocardial infarction.METHODSCoronary snares and sonomicrometry crystals in remote and area-at-risk regions were placed in pigs (n = 22, 34 kg). Geometric measurements at end diastole and end systole, including left ventricular area by echocardiography and interregional distance by sonomicrometry, were obtained at baseline. Coronary occlusion was instituted for 60 minutes, followed by reperfusion and repeated geometric measurements at 7 days, including left ventriculography. At reperfusion, pigs were randomized to saline (n = 12) or caspase inhibition (n = 10, IDN6734, 2 mg/kg intravenously, then 2 mg x kg x h for 24 hours) at a dose that achieved desired plasma concentrations (790 +/- 142 ng/mL) as predicted by prior pharmacokinetic studies.RESULTSInfarct size and 24-hour troponin-I values were not significantly different between the saline and caspase inhibition groups (51% +/- 8% vs 42% +/- 6% and 189 +/- 20 ng/mL vs 152 +/- 26 ng/mL, respectively, P >.10). At 7 days, end-diastole volume was increased in both groups compared with reference control values (47 +/- 1 mL, P <.05), but it was decreased with caspase inhibition (72 +/- 4 mL) compared with saline (84 +/- 4 mL, P <.05). Similarly, end-diastole and end-systole areas increased by 32% +/- 3% and 81% +/- 16% in the saline group but were attenuated with caspase inhibition (19% +/- 3% and 31% +/- 10%, respectively, P <.05). End-diastole interregional distance increased by 30% +/- 7% in the saline group but was attenuated with caspase inhibition (12% +/- 5%, P <.05).CONCLUSIONDespite equivalent degrees of myocardial injury, caspase inhibition reduced post-myocardial infarction left ventricular remodeling as evidenced by multiple, independent assessments of left ventricular dilation. Thus, caspase activation alters left ventricular geometry in the absence of significant effects on myocardial injury.

01 Aug 2002·Journal of Biological ChemistryQ2 · BIOLOGY

Calpain and Mitochondria in Ischemia/Reperfusion Injury

Q2 · BIOLOGY

Article

Author: Roberta A. Gottlieb ; Stan Krajewski ; Dong-Jun Won ; Min Chen

Studies of ischemia/reperfusion (I/R) injury and preconditioning have shown that ion homeostasis, particularly calcium homeostasis, is critical to limiting tissue damage. However, the relationship between ion homeostasis and specific cell death pathways has not been investigated in the context of I/R. Previously we reported that calpain cleaved Bid in the absence of detectable caspase activation (1). In this study, we have shown that an inhibitor of the sodium/hydrogen exchanger prevented calpain activation after I/R. Calpain inhibitors prevented cleavage of Bid as well as the downstream indices of cell death, including DNA strand breaks, creatine kinase (CK) release, and infarction measured by triphenyl tetrazolium chloride (TTC) staining. In contrast, the broad spectrum caspase inhibitor IDN6734 was not protective in this model. To ascertain whether mitochondrial dysfunction downstream of these events was a required step, we utilized a peptide corresponding to residues 4-23 of Bcl-x(L) conjugated to the protein transduction domain of HIV TAT (TAT-BH4), which has been shown to protect mitochondria against Ca2+-induced deltaPsi(m) loss (2). TAT-BH4 attenuated CK release and loss of TTC staining, demonstrating the role of mitochondria and a pro-apoptotic Bcl-2 family member in the process leading to cell death. We propose the following pathway. (i) Reperfusion results in sodium influx followed by calcium accumulation. (ii) This leads to calpain activation, which in turn leads to Bid cleavage. (iii) Bid targets the mitochondria, causing dysfunction and release of pro-apoptotic factors, resulting in DNA fragmentation and death of the cell. Ischemia/reperfusion initiates a cell death pathway that is independent of caspases but requires calpain and mitochondrial dysfunction.

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Indication	Highest Phase	Country/Location	Organization	Date
Ischemia	Preclinical	US	The Scripps Research Institute	09 Aug 2002
Myocardial Infarction	Preclinical	US	Idun Pharmaceuticals, Inc.	-

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