Table 2.
Summary of phenotypes observed in animal models of cardiovascular diseases in relation to modification of the TNF-α signaling pathway.
| Model | Transgene/Intervention | Phenotype | Ref. |
|---|---|---|---|
| Overexpression | |||
| Cardiomyocyte-specific TNF-α overexpression | none | Lethal myocarditis with interstitial edema | [80] |
| none | Progressive heart failure with severe LV remodeling | [81] | |
| none | Calcium-dependent atrial and ventricular arrhythmias | [82] | |
| sTNFR1 overexpression | Preservation of LV function | [83] | |
| Tnfrsf1a −/− | Improved cardiac function, reduced mortality | [85] | |
| Tnfrsf1b −/− | Exacerbated heart failure, increased mortality | ||
| Cardiomyocyte-specific mTNF-α overexpression | none | Cardiac hypertrophy without inflammation and systolic dysfunction | [86] |
| Atherosclerosis | |||
| Atherogenic diet | Tnfa −/− | Protection from atherosclerotic lesion formation, lowered atherogenic lipid profile, decreased IL-6 levels | [99] |
| Exclusive expression of mTNF-α | Partial protection from atherosclerosis. Lower lipid deposition and macrophage accumulation, no changes in atherogenic lipid profile and IL-6 | ||
| Apoe−/− on atherogenic diet | Tnfa −/− | Slower plaque growth, decreased atherosclerotic markers, no changes in cholesterol levels | [88,89] |
| Tnfa −/− | Reduced plaque growth | [91] | |
| sTNFR1 treatment | Reduced plaque growth | ||
| Transplantation of Tnfa−/− bone marrow | Reduced plaque growth | ||
| Tnfrsf1a−/− grafted arteries | Reduced plaque growth and adhesion molecule expression | [101] | |
| Weekly infliximab injections | Improved endothelial functions, reduced atherosclerotic plaques, and decreased ROS | [93] | |
| Single injection of DC-derived mTNF-bearing exosomes | Increased levels of adhesion molecules in lesions, increased plaque formation | [96] | |
| Apoe*3-Leiden on atherogenic diet | Tnfa −/− | Higher number of early lesions and lower number of advanced lesions. Decreased necroptosis and increased apoptosis in lesion area. No changes in inflammatory parameters and lipid profiles | [90] |
| Ldlr−/− on atherogenic diet | ADAM17 deficiency(increased mTNF and permanent TNFR2 activation) | Faster plaque growth, enhanced macrophage adhesion, increased macrophage, and smooth muscle proliferation | [98] |
| Etanercept in combination with pravastatin/saprogrelate therapy | Decrease in aortic lesion area, endothelial adhesion molecules, and improved lipid profile in comparison to pravastatin/saprogrelate | [94] | |
| Monoclonal anti-mouse TNF-α antibody administration | Reduced plaque stability, increased vascular pro-inflammatory gene expression, and larger plaque area | [95] | |
| Recombinant TNF-α administration | Increased plaque burden and endothelial LDL transcytosis. Prevented by pharmacological NF-κB inhibitors | [92] | |
| Myocardial Infarction | |||
| Permanent occlusion | Tnfa −/− | Lower infarct area, less infiltrating mononuclear cells, reduced expression of endothelial adhesion molecules at day 1 and 7 | [103] |
| Improved cardiac functions up to 3 days, but not at day 7 | [113] | ||
| Tnfrsf1a −/− | Improved contractile functions, diminished hypertrophy and remodeling, reduced NF-κB activation after 4 weeks | [110] | |
| Lower infarct area and fibrosis, preserved cardiac functions at day 7 | [113] | ||
| Improved contractile functions, increased survival rate after 4 weeks | [111] | ||
| Protection for infarction-induced death, improved LV functions, and decreased hypertrophy after 6 weeks | [112] | ||
| Reduced mortality 24 h post infarction, lower inflammation, and improved cardiac recovery after 28 days | [123] | ||
| Pharmacological TNFR1 inactivation in subfornical organ | Reduced LV dysfunction after 4 weeks | [115] | |
| Tnfrsf1b −/− | Worsened remodeling, hypertrophy and contractile functions, increased fibrosis and apoptosis at day 28 | [110] | |
| Worsened cardiac functions, increased infarct size, exacerbated fibrosis at day 3 and 7 | [113] | ||
| Exacerbated hypertrophy, fibrosis, ventricular dilatation, and dysfunction after 4 weeks | [111] | ||
| Increased mortality during the first 7 days, reduced number of functional blood vessels in infarct area after 28 days | [123] | ||
| Daily monoclonal anti-TNF-α antibody administration during the first week after myocardial infarction | Reduced inflammation, worsened cardiac functions, inhibited autophagy and increased apoptosis in cardiomyocytes after 1, 2, 3, and 4 weeks | [108] | |
| Single etanercept injection directly after myocardial infarction | Reduced inflammation, improved remodeling, and preserved LV functions after 4 days | [107] | |
| Ischemia-reperfusion | Tnfa −/− | Lower infarct area, improved cardiac functions, reduced cardiac NF-κB activation measured 120 min from reperfusion | [105] |
| Etanercept administration 10 min prior to myocardial infarction | Lower infarct area, improved cardiac functions, 3 h, 24 h, or 14 days after reperfusion | [106] | |
| Anti-mouse TNF-α antibody injection 3 h prior myocardial infarction | Preserved endothelial functions, reduced endothelial production of ROS 90 min after reperfusion | [109] | |
| Hypertrophic Cardiomyopathy | |||
| Transverse aortic constriction | Tnfa −/− | Reduced inflammatory response, decreased hypertrophy, improved cardiac functions | [121] |
| Tnfa −/− Timp3 −/− | Attenuated LV dilation, improved cardiac functions, increased survival after 7 weeks. Complete prevention of heart disease upon additional MMP inhibitors administration | [120] | |
| Tnfa −/− | Improved cardiac functions, suppression of MMPs expression, reduction in superoxide production | [122] | |
| Tnfrsf1b −/− | Increased survival rates, decreased hypertrophy, improved mitochondrial functions | [124] | |
| Tradd−/− | Reduced hypertrophy with improved cardiac functions, attenuated TAK1/p38 MAPK phosphorylation | [125] | |
| Tnfrsf1a −/− Tnfrsf1b −/− | Increased mortality, hypertrophy, and mitochondrial DNA damage | [124] | |
| Traf2−/− | TNFR1-dependent pathological remodeling and increased cardiomyocyte death | [30] | |
| Angiotensin II-induced hypertrophy | Tnfa −/− | Reduced hypertrophy and hypertension | [126] |
| Tnfrsf1a −/− | Slower progression of hypertrophy, reduced fibrosis and immune response | [127] | |
| Tnfrsf1a −/− | No effect on early inflammatory phase, increased uptake of bone marrow-derived fibroblasts progenitors and exacerbated fibrosis | [128] | |
| Tnfrsf1b −/− | No effects | [128] | |
| Isoproterenol-induced hypertrophy | Tnfrsf1a −/− | Reduced inflammatory response at day 1, unchanged hypertrophy at day 7 | [129] |
| Tnfrsf1b −/− | Increased inflammatory response at day 1, exacerbated hypertrophy at day 7 | ||
| Alcoholic cardiomyopathy | Tnfrsf1a −/− | Preserved LV functions, decreased ROS in LV, lower serum levels of TNF-α | [131] |
| Inflammatory Heart Diseases | |||
| Coxsackievirus B3 induced myocarditis | Tnfa −/− | Reduced myocarditis, no changes in virus titers | [134] |
| Tnfrsf1a −/− | Reduced myocarditis, no changes in virus titers | ||
| Tnfrsf1b −/− | Unaffected myocarditis, no changes in virus titers | ||
| Myocarditis induced by cardiac myosin immunization | Anti-TNF-α/β before immunization | Reduced myocarditis | [135] |
| Anti-TNF-α/β after immunization | Unaffected myocarditis | ||
| Tnfrsf1a −/− | Protection from myocarditis despite of T cell activation | [136] | |
| Myocarditis induced by autoreactive T cell transfer | Tnfrsf1a −/− | Protection from myocarditis | |
LDL: low-density lipoprotein LV: left ventricular, MMP: matrix metalloproteinase, ROS: reactive oxygen species, Timp3−/−: metalloproteinase inhibitor 3 knockout, Tnfa−/−: tumor necrosis factor-α knockout, Tnfrsf1a−/−: TNFR1 knockout, Tnfrsf1b−/−: TNFR2 knockout, TRADD−/−: tumor necrosis factor receptor type 1-associated death domain protein knockout.