Matrix Metalloproteinase Inhibitors Attenuate Doxorubicin‐Induced Heart Failure by Preventing Cardiac Titin Proteolysis
Bibliographic record
Abstract
Heart failure remains a major, long‐term complication with doxorubicin (DXR) cancer chemotherapy. We investigated the mechanism of DXR cardiotoxicity in order to develop new strategies to prevent heart injury when treating cancer patients. The cardiotoxicity of DXR is associated with increased oxidative stress in cardiomyocytes. Intracellular matrix metalloproteinase‐2 (MMP‐2) activity is enhanced by oxidative stress by two means: a) direct activation of 72 kDa MMP‐2 by peroxynitrite‐mediated S‐glutathiolation and, b) de novo expression of an N‐terminal truncated isoform (NTT‐MMP‐2). We have shown that MMP‐2 is enriched in the Z‐disc of the sarcomere where it cleaves titin following oxidative stress caused by ischemia‐reperfusion injury. We determined whether MMP‐2 mediated titin proteolysis contributes to DXR‐induced heart failure in vivo. 8‐week old male C57BL/6J mice were treated with DXR weekly (6 mg/kg, i.p.) or saline vehicle (control) ± MMP inhibitors (by daily gavage) doxycycline (15 mg/kg) or ONO‐4817 (60 mg/kg) for 4 weeks. Cardiac function was assessed by M‐mode echocardiography before and after treatment (n=10 mice per group) and then the hearts were collected for biochemical analysis. MMP‐2 mRNA expression, protein levels, and activity were measured by qPCR, Western blot and gelatin zymography, respectively. N2BA and N2B titin isoforms and the primary titin degradation product levels were measured by agarose gel electrophoresis. DXR caused systolic and diastolic dysfunction marked by a significant reduction in left ventricular ejection fraction (64±2% vs. 45±2%, p<0.05), fractional shortening (35±2% vs. 22±1%, p<0.05), and E′/A′ ratio (1.07±0.04 vs. 0.85±0.06, p<0.05) compared to control. Doxycycline or ONO‐4817 prevented these changes. DXR caused significant cardiac remodeling including the thinning of the posterior wall (0.99±0.03 vs 1.16±0.04 mm, p<0.05) and increased left ventricular internal diameter (2.93±0.09 vs 2.55±0.09 mm, p<0.05) during systole, an effect that was prevented by doxycycline, but not ONO‐4817. DXR upregulated NTT‐MMP‐2 mRNA in the heart to 195±16% (p<0.05) of control and increased MMP‐2 protein levels (149±19% vs. control, p<0.05), accompanied by a trend to increased MMP‐2 gelatinolytic activity (200±14% vs. control, p=0.06). These biochemical changes were prevented by doxycycline or ONO‐4817. DXR did not alter cardiac titin isoform expression (N2BA:N2B) in the heart but increased titin degradation (T2/T1 ratio) to 258±7% (p<0.05) which was reduced by ONO‐4817 (169±10%) but not doxycycline (203±16%). MMP‐2 activation contributes to DXR‐induced heart failure in mice by proteolyzing cardiac titin in an MMP‐2‐dependent manner. Moreover, two orally available MMP inhibitors prevented heart failure, suggesting that their use may be a potential prophylactic strategy to prevent heart during cancer chemotherapy. Support or Funding Information Canadian Institutes of Health Research (to RS); Women and Children's Health Research Institute Graduate Studentship (to BC). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".