Long-Term caspase inhibition ameliorates apoptosis, reduces myocardial troponin-I cleavage, protects left ventricular function, and attenuates remodeling in rats with myocardial infarction
Y. Chandrashekhar, MD*,*,
Soma Sen, MD*,
Ruth Anway, BA*,
Allan Shuros, BS* and
Inder Anand, FRCP, DPhil(Oxon), FACC*
* Division of Cardiology, VA Medical Center and University of Minnesota, Minneapolis, Minnesota, USA
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Figure 1 (Top) Representative Western blot showing reduced caspase 3 and troponin-I cleavage in caspase inhibitor treated rats. Arrows identify the cleaved fragment. (Bottom) Mean density units normalized to actin (n = 8 each group) for caspase 3 and troponin-I cleaved fragments. Control = vehicle treated rats.
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Figure 2 (A) Immunostaining for activated caspases in cardiomyocytes. Representative sections of left ventricular myocardium (200 to 400x). The left panel shows Apologix carboxyfluorescein activated caspase stain (white spots in panel A) and the same field stained with alpha sarcomeric actin (B) below. Most of the apoptotic cells were myocytes. One fibroblast with apoptosis is also shown (arrowhead in panels A and B) and has a different morphology. The next two panels show the effect of caspase inhibitors (caspase Rx) on number of apoptotic cells measured with Apologix staining (seen as large white bright spots in panels C and D) or TUNEL (greenish color in panels E and F). There were fewer (panels C and E) activated caspase-positive cells (panel C) or TUNEL-positive cells (panel E) in the myocardium of animals treated with caspase inhibitors than in the myocardium of animals with vehicle treatment (no caspase Rx, panels D and F). (B) Mean data for the number of apoptotic cardiomyocytes from rats with myocardial infarction treated or not treated with the caspase inhibitor (n = 8 each group).
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Figure 3 Systolic function was better preserved both at one week and four weeks after myocardial infarction (MI) in caspase inhibitor (CI) treated (MI + CI, n = 12) rats than in vehicle (dimethyl sulfoxide) treated (MI + DMSO, n = 9) rats or MI rats without any pump (untreated MI, n = 15). Systolic function still remained worse than in sham-operated animals (n = 17). EF = ejection fraction; FS = fractional shortening.
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Figure 4 Left ventricular (LV) remodeling and function were improved in rats with myocardial infarction (MI) given a caspase inhibitor (MI + CI, n = 12) for four weeks compared with vehicle (dimethyl sulfoxide) treated (MI + DMSO, n = 9) rats or MI rats without any pump (untreated MI, n = 15). Left ventricular remodeling still remained worse than in sham-operated animals (n = 17).
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