Table 3.
The effects of TLR4 inhibition in Dox-induced cardiotoxicity: reports from in vivo studies.
| Model | Protocol (Dose, Duration) |
Intervention of TLR4 Inhibition (Agent, Dose, Route, Duration) | Major Findings | Interpretation | Ref. | ||||
|---|---|---|---|---|---|---|---|---|---|
| Cardiac Function | Inflammatory Markers | Cardiac Remodeling/Fibrosis | Oxidative Stress | Apoptosis | |||||
| C57BL/6J mice | Dox (20 mg/kg, i.p., single dose) -Sacrifice on day 5 |
TLR4−/− | ↑ LVESPVR | n/a | n/a | n/a | ↓ TUNEL+ | TLR4 deficiency attenuated Dox-induced cardiac apoptosis and dysfunction in mice. | [31] |
| C57BL/10ScSn mice | Dox (20 mg/kg, i.p., single dose) -Sacrifice on day 5 |
TLR4−/− | ↑ SV ↑ CO |
↓ TNF-α ↓ CD3+ ↓ CD11b+ ↓ CD8a+ |
n/a | ↓ Lipid peroxidation ↓ Nitrotyrosine |
↓ Bax ↑ Bcl-2 ↓ TUNEL+ |
TLR4 deficiency rescued Dox-induced cardiotoxicity in mice. | [22] |
| C57BL/6J mice | Dox (3.4 mg/kg/wk, i.p., 8 wk) -Sacrifice on day 103 |
TLR4ab (first dose was 200 µg/mg and following doses were 100 µg/mg, tv.i., on day 64, 68, 72, 79, 86, 96, and 100 after Dox injection) | ↓ %LVEF ↓ %LVFS |
↔TLR4 ↔ HMGB1 ↔ Hsp70 ↑ MCP-1 ↑ IL-13 ↑ TGF-β1 |
↑ Fibrosis ↑ α-SMA |
n/a | n/a | Immunomodulation of TLR4 exacerbated cardiac dysfunction in Dox-treated mic by increasing inflammation and fibrosis. | [40] |
| C57BL/6J mice | Dox (15 mg/kg, i.p., single dose) -Sacrifice on day 21 |
AAV-Hsp22 (5 × 1010 viral genome particles, tv.i., single dose, before Dox injection for 4 wk) |
↑ %LVEF | ↓ TLR4 ↓ TNF-α ↓ IL-6 ↓ NF-kB ↓ CD68 ↓ CD45 |
n/a | n/a | ↓ Bax ↑ Bcl-2 ↓ Cyt c ↓ TUNEL+ |
Hsp22 protected the heart against Dox-induced cardiotoxicity via inhibited TLR4/NF-kB signaling pathway in mice. | [14] |
| Wistar rats | Dox (2.5 mg/kg/3 doses/wk, i.p., 2 wk) -Sacrifice on day 28 |
VA (10, 20, and 40 mg/kg/d, p.o., 4 wk, before Dox injection for 14 days) |
n/a | ↓ TLR4 | n/a | ↓ MDA | n/a | VA protected the heart against Dox-induced cardiotoxicity via inhibited TLR4 signaling pathway in rats. | [23] |
n/a: Data are not available; AAV-Hsp22: adeno-associated virus–heat shock protein 22; Bax: Bcl-2-associated X; Bcl-2: B-cell lymphoma-2; CO: cardiac output; Cyt c: cytochrome c; Dox: doxorubicin; HMGB1: high-mobility group box 1; Hsp70: heat shock protein 70; i.p.: intraperitoneal injection; IL-13: interleukin 13; IL-6: interleukin-6; LVEF: left ventricular ejection fraction; LVESPVR: left ventricular end-systolic pressure-volume relation; LVFS: left ventricular fractional shortening; MCP-1: monocyte chemotactic protein 1; MDA: malondialdehyde; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; p.o.: per orally; SV: stroke volume; TGF-β1: tumor growth factor β1; TLR4: Toll-like receptor 4; TNF-α: tumor necrosis factor-alpha; TUNEL: terminal deoxynucleotidyl transferase mediated dUTP nick end labeling; tv.i.: tail vein injection; VA: vanillic acid; α-SMA: α-smooth muscle actin; ↑: Increase; ↓: Decrease; ↔: No change.