Table 3.
Effects of death pathway manipulations in cardiac disease models and humans
| Pathways | Cell Type | Cardiac Disease Model | Outcomes | Reference Nos. |
|---|---|---|---|---|
| Death receptor pathway in MI | ||||
| Fas –/– (lpr mutant) | Global | I/R (in vivo) | Reduced infarct size | 258 |
| Tnfr1 –/– | Global | MI without reperfusion (in vivo) | No change in infarct size | 250 |
| Tnfr2 –/– | Global | MI without reperfusion (in vivo) | No change in infarct size | 250 |
| Tnfr1 –/–; Tnfr2 –/– | Global | MI without reperfusion (in vivo) | Increased infarct size | 250 |
| Necrostatin-1 (WT mice) | I/R (in vivo) | Reduced infarct size | 448 | |
| Necrostatin-1 (global ppif –/– mice) | I/R (in vivo) | No additional reduction in infarct size | 272 | |
| Ripk3 –/– | Global | I/R (in vivo) | Reduced infarct size | 351, 563 |
| miR-103/107 antagomir | I/R (in vivo) | Reduced infarct size and necrosis | 507 | |
| miR-873 | I/R (in vivo) | Reduced infarct size and necrosis | 508 | |
| NRF-siRNA | I/R (in vivo) | Reduced infarct size and necrosis | 508 | |
| miR-223 tg overexpression | Cardiomyocyte | I/R (in vivo) | Reduced infarct size and necrosis | 388 |
| miR-223 –/– | Global | I/R (in vivo) | Increased infarct size and necrosis | 388 |
| Mitochondrial pathway in MI | ||||
| Bcl-2 tg overexpression | Cardiomyocyte | I/R (in vivo) | Reduced infarct size | 38, 54 |
| Bax –/– | Global | I/R (isolated perfused) | Reduced infarct size, apoptosis, and necrosis | 192 |
| Bax –/– | Global | MI without reperfusion (in vivo) | Reduced infarct size and post MI dysfunction | 191 |
| Bax –/–; Bak –/– | Bax (cardiomyocyte) | I/R (in vivo) | Reduced infarct size, apoptosis, and necrosis | 528 |
| Bak (global) | ||||
| Ppif –/– | Global | I/R (in vivo) | Reduced infarct size and necrosis | 17, 341 |
| Ppif tg overexpression | Cardiomyocyte | Baseline (in vivo) | Necrosis | 17 |
| Ppif –/– + Bax –/–; Bak –/– | Bax (cardiomyocyte) | I/R (in vivo) | No additional reduction in infarct size | 528 |
| Bak (global) | ||||
| Ppif (global) | ||||
| Puma –/– | Global | I/R (isolated perfused) | Reduced infarct size, apoptosis, and necrosis | 483 |
| Cyclosporine A | I/R (various models) | Reduced infarct size (with some variability) | 367, 273 | |
| Cyclosporine A (humans) | I/R (in vivo) | Reduced infarct size | 381 | |
| Cyclosporine A (humans) | I/R (in vivo) | No reduction in infarct size or post MI dysfunction | 69 | |
| Death receptor and mitochondrial pathways in MI | ||||
| cIAP2 tg overexpression | Cardiomyocyte | I/R (in vivo) | Reduced infarct size, apoptosis, and necrosis | 62 |
| UCF-101 | I/R (in vivo) | Reduced infarct size | 24, 282 | |
| ARC tg overexpression | Cardiomyocyte | I/R (in vivo) | Reduced infarct size | 386 |
| Caspase inhibitors | I/R (in vivo) | Reduced infarct size | 195, 198, 538, 544 | |
| Procaspase-3 –/– | Procaspase-3 (cardiomyocyte) | I/R (in vivo) | No reduction in infarct size or post MI dysfunction | 206 |
| Procaspase-7 –/– | Procaspase-7 (global) | |||
| Death receptor pathway in HF | ||||
| Procaspase-8 tg overexpression | Cardiomyocyte | Baseline (in vivo) | 0.023% TUNEL+ cardiomyocytes (control 0.002%) | 524 |
| (limited activation) | Lethal heart failure | |||
| Procaspase-8 tg overexpression | Cardiomyocyte | Baseline (in vivo) | Rescue of TUNEL positivity and heart failure | 524 |
| (limited activation + delayed caspase inhibition) | ||||
| Traf2 –/– | Cardiomyocyte | Baseline (in vivo) | Dilated cardiomyopathy and heart failure | 169 |
| Traf2 +/– | Cardiomyocyte | MI without reperfusion (in vivo) | Dilated cardiomyopathy and heart failure | 169 |
| Traf2 –/–; Tnfr1 –/– | Traf2 (cardiomyocyte) | Baseline (in vivo) | Rescued pathological phenotype of Traf2 –/– | 169 |
| Tnfr1 (global) | ||||
| Traf2 –/–; Ripk3 –/– | Traf2 (cardiomyocyte) | Baseline (in vivo) | Rescued pathological phenotype of Traf2 –/– | 169 |
| Ripk3 (global) | ||||
| Tak1 –/– | Cardiomyocyte | Baseline (in vivo) | Dilated cardiomyopathy and heart failure | 265 |
| Tak1 –/–; Tnfr1 –/– | Tak1 (cardiomyocyte) | Baseline (in vivo) | Rescued pathological phenotype of Tak1 –/– | 265 |
| Tnfr1 (global) | ||||
| Ripk3 –/– | Global | MI without reperfusion (in vivo) | Reduced cardiac remodeling and heart failure | 298 |
| Ripk3 –/– | Global | Doxorubicin | Reduced cardiac dysfunction | 563 |
| Mitochondrial pathway in HF | ||||
| L-type Ca2+channel (LTCC) tg overexpression | Cardiomyocyte | Baseline (in vivo) | Ca2+ overload, necrosis, heart failure, premature death. | 346 |
| LTCC tg overexpression | LTCC (cardiomyocyte) | Baseline (in vivo) | Rescued heart failure | 346 |
| Ppif –/– | Ppif (global) | |||
| Ppif –/– | Global | Doxorubicin | Decreased cardiac dysfunction and necrosis | 346 |
| Ppif -/ | Global | Pressure overload | Dilated cardiomyopathy and heart failure | 114 |
| Shift from fatty acid to glucose use | ||||
| Ppif –/– | Global | Swimming | Mortality in 5 days | 114 |
| Increased hypertrophy and pulmonary edema | ||||
| Bnip3 –/– | Global | I/R (in vivo) | Reduced apoptosis, cardiac remodeling, and heart failure | 96 |
| Bnip3 –/– | Global | Doxorubicin | Reduced mitochondrial abnormalities and mortality | 90 |
| Bnip3 tg overexpression | Cardiomyocyte | Baseline (in vivo) | Pathological remodeling and heart failure | 96 |
| Gαq tg overexpression | Cardiomyocyte | Baseline (in vivo) | Increased apoptosis, hypertrophy, and heart failure | 3, 71 |
| Gαq tg overexpression | Cardiomyocyte | Pregnancy | Heart failure | 3 |
| Gαq tg overexpression + caspase inhibition | Cardiomyocyte | Pregnancy | Rescued heart failure | 180 |
| NIX/BNIP3L tg overexpression | Cardiomyocyte | Baseline (in vivo) | Increased apoptosis and heart failure | 557 |
| Gαq tg overexpression | Cardiomyocyte | Baseline (in vivo) | Rescued apoptosis and heart failure | 557 |
| Autophagy-dependent cell death | ||||
| Beclin-1 +/– | Global | Pressure overload | Reduced autophagy and cardiac dysfunction | 570 |
| Beclin-1 tg overexpression | Cardiomyocyte | Pressure overload | Increased autophagy and cardiac dysfunction | 570 |
| Beclin-1 +/– | Global | I/R (in vivo) | Reduced autophagy and infarct size | 310 |
| Beclin-1 +/– | Beclin (global) | Baseline (in vivo) | Accelerated heart failure and early mortality | 475 |
| Desmin tg overexpression | Desmin (cardiomyocyte) | |||
| Atg5 –/– (postnatal) | Cardiomyocyte | Baseline (in vivo) | Heart failure and TUNEL+ cardiomyocytes | 344 |
| Atg5 –/– (embryonic) | Cardiomyocyte | Pressure overload | Heart failure | 344 |
| Ferroptosis | ||||
| Deferoxamine (iron chelator) | Perfusion | I/R (isolated perfused) | Reduced infarct size | 144 |
| Glutaminolysis inhibitor | Perfusion | I/R (isolated perfused) | Reduced infarct size | 144 |
| GPX4 tg overexpression (mitochondrial targeted) | Global | I/R (isolated perfused) | Reduced release of creatine kinase | 72 |
| Ferrostatin-1 | I/R (in vivo) | Reduced infarct size and myocardial enzyme release | 120, 268 | |
| Cardiac dysfunction and pathological remodeling | ||||
| Ferrostatin-1 | Doxorubicin | Reduced cardiac dysfunction | 120 | |
| Ferrostatin-1 | Heart transplantation | Reduced cardiac cell death | 268 | |
| Dexrazoxane | I/R (in vivo) | Reduced infarct size and myocardial enzyme release | 120 | |
| Dexrazoxane | Doxorubicin | Reduced cardiac dysfunction | 120 | |
| Pyroptosis | ||||
| Caspase-1 –/– | Global | I/R (in vivo) | Reduced infarct size | 229 |
| Caspase-1 –/– | Global | MI without reperfusion (in vivo) | Reduced cardiac dysfunction | 317 |
| Caspase-1 tg overexpression | Cardiomyocyte | Baseline (in vivo) | Heart failure | 317 |
| Caspase-1 tg overexpression | Cardiomyocyte | I/R (in vivo) | Increased infarct size | 467 |
| ASC –/– | Global | I/R (in vivo) | Reduced infarct size | 229 |
| ASC –/– bone marrow | ASC (global) | I/R (in vivo) | Reduced infarct size compared with WT | 229 |
| Into WT mice | Same infarct size compared with ASC –/– | |||
| WT bone marrow | ASC (global) | I/R (in vivo) | Reduced infarct size compared with WT | 229 |
| into ASC –/– mice | Same infarct size compared with ASC –/– | |||
| Parthanatos | ||||
| Parp-1 –/– | Global | I/R (isolated perfused) | Reduced cardiac contractile dysfunction | 165, 378, 567 |
| Parp-1 –/– | Global | I/R (in vivo) | Reduced infarct size and myocardial enzyme release | 543, 573 |
| PARP-1 inhibitor | I/R (in vivo) | Reduced infarct size | 269, 378, 517, 572 | |
| PARP-1 inhibitor | Perfusion | I/R (isolated perfused) | Reduced cardiac contractile dysfunction | 98, 567 |
| Parp-1 –/– | Global | Pressure overload | Reduced pathological remodeling | 379 |
| Mif –/– | Global | I/R (in vivo) | Increased infarct size | 324, 387 |
| Mif –/– | Global | I/R (isolated perfused) | Increased infarct size | 387 |
I/R, ischemia/reperfusion; MI, myocardial infarction; tg, transgenic.