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BackgroundHeart failure (HF) presents a massive burden to health care with a complex pathophysiology that results in HF with reduced left ventricle ejection fraction (EF) or HF with preserved EF. It has been shown that relatively modest changes in protein glycosylation, an essential posttranslational modification, are associated with clinical presentations of HF. We and others previously showed that such aberrant protein glycosylation in animal models can lead to HF. Methods and ResultsWe develop and characterize a novel, tamoxifen‐inducible, cardiomyocyteMgat1knockout mouse strain, achieved through deletion ofMgat1, alpha‐1,3‐mannosyl‐glycoproten 2‐beta‐N‐acetlyglucosaminyltransferase, which encodes N‐acetylglucosaminyltransferase I. We investigate the role of hybrid/complex N‐glycosylation in adult HFrEF pathogenesis at the ion channel, cardiomyocyte, tissue, and gross cardiac level. The data demonstrate successful reduction of N‐acetylglucosaminyltransferase I activity and confirm that hybrid/complex N‐glycans modulate gating of cardiomyocyte voltage‐gated calcium channels. A longitudinal study shows that the tamoxifen‐inducible, cardiomyocyteMgat1knockout mice present with significantly reduced systolic function by 28 days post induction that progresses into HFrEF by 8 weeks post induction, without significant ventricular dilation or hypertrophy. Further, there was minimal, if any, physiologic or pathophysiologic cardiomyocyte electromechanical remodeling or fibrosis observed before (10–21 days post induction) or after (90–130 days post induction) HFrEF development. ConclusionsThe tamoxifen‐inducible, cardiomyocyteMgat1knockout mouse strain created and characterized here provides a model to describe novel mechanisms and causes responsible for HFrEF onset in the adult, likely occurring primarily through tissue‐level reductions in electromechanical activity in the absence of (or at least before) cardiomyocyte remodeling and fibrosis.
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Beneficial Effects of Oral Carbon Monoxide on Doxorubicin‐Induced Cardiotoxicity
BackgroundDoxorubicin and other anthracyclines are crucial cancer treatment drugs. However, they are associated with significant cardiotoxicity, severely affecting patient care and limiting dosage and usage. Previous studies have shown that low carbon monoxide (CO) concentrations protect against doxorubicin toxicity. However, traditional methods of CO delivery pose complex challenges for daily administration, such as dosing and toxicity. To address these challenges, we developed a novel oral liquid drug product containing CO (HBI‐002) that can be easily self‐administered by patients with cancer undergoing doxorubicin treatment, resulting in CO being delivered through the upper gastrointestinal tract. Methods and ResultsHBI‐002 was tested in a murine model of doxorubicin cardiotoxicity in the presence and absence of lung or breast cancer. The mice received HBI‐002 twice daily before doxorubicin administration and experienced increased carboxyhemoglobin levels from a baseline of ≈1% to 7%. Heart tissue from mice treated with HBI‐002 had a 6.3‐fold increase in CO concentrations and higher expression of the cytoprotective enzyme heme oxygenase‐1 compared with placebo control. In both acute and chronic doxorubicin toxicity scenarios, HBI‐002 protected the heart from cardiotoxic effects, including limiting tissue damage and cardiac dysfunction and improving survival. In addition, HBI‐002 did not compromise the efficacy of doxorubicin in reducing tumor volume, but rather enhanced the sensitivity of breast 4T1 cancer cells to doxorubicin while simultaneously protecting cardiac function. ConclusionsThese findings strongly support using HBI‐002 as a cardioprotective agent that maintains the therapeutic benefits of doxorubicin cancer treatment while mitigating cardiac damage.
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- Award ID(s):
- 1927616
- PAR ID:
- 10565949
- Publisher / Repository:
- Wiley
- Date Published:
- Journal Name:
- Journal of the American Heart Association
- Volume:
- 13
- Issue:
- 9
- ISSN:
- 2047-9980
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1161/JAHA.123.032067
