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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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Cold‐induced fibrosis and metabolic remodeling in the turtle ( Trachemys scripta ) ventricle
Abstract AimCardiac fibrosis contributes to systolic and diastolic dysfunction and can disrupt electrical pathways in the heart. There are currently no therapies that prevent or reverse fibrosis in human cardiac disease. However, animals like freshwater turtles undergo seasonal remodeling of their hearts, demonstrating the plasticity of fibrotic remodeling. InTrachemys scripta, cold temperature affects cardiac load, suppresses metabolism, and triggers a cardiac remodeling response that includes fibrosis. MethodsWe investigated this remodeling using Fourier transform infrared (FTIR) imaging spectroscopy, together with functional assessment of muscle stiffness, and molecular, histological, and enzymatic analyses in control (25°C)T. scriptaand after 8 weeks of cold (5°C) acclimation. ResultsFTIR revealed an increase in absorption bands characteristic of protein, glycogen, and collagen following cold acclimation, with a corresponding decrease in bands characteristic of lipids and phosphates. Histology confirmed these responses. Functionally, micromechanical stiffness of the ventricle increased following cold exposure assessed via atomic force microscopy (AFM) and was associated with decreased activity of regulatory matrix metalloproteinases (MMPs) and increased expression of MMP inhibitors (TMPs) which regulate collagen deposition. ConclusionsBy defining the structural and metabolic underpinnings of the cold‐induced remodeling response in the turtle heart, we show commonalities between metabolic and fibrotic triggers of pathological remodeling in human cardiac disease. We propose the turtle ventricle as a novel model for studying the mechanisms underlying fibrotic and metabolic cardiac remodeling.
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- Award ID(s):
- 1755187
- PAR ID:
- 10590607
- Publisher / Repository:
- John Wiley & Sons Ltd
- Date Published:
- Journal Name:
- Acta Physiologica
- Volume:
- 241
- Issue:
- 4
- ISSN:
- 1748-1708
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript
- Journal Article:
- https://doi.org/10.1111/apha.70026
