SAMD1 Distribution Patterns in Mouse Atherosclerosis Models Suggest Roles in LDL Retention, Antigen Presentation, and Cell Phenotype Modulation
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Abstract
The theory that lesions formed by retention of circulating LDL can then progress to complicated atherosclerotic lesions has been a subject of debate, as has the mechanism of retention. In earlier work, we identified SAMD1, a protein expressed by intimal smooth muscle cells in human lesions that appears to irreversibly bind apoB-Lps in extracellular matrix near the lumen. We hypothesized this binding could contribute to the formation of lesions in mice, and that inhibiting binding could reduce lesion growth. In mouse models of atherosclerosis, we found that SAMD1 binds LDL; that SAMD1/apoB complex is ingested by intimal cells; and that recognizable epitopes of the SAMD1/apoB complex survive some degree of catabolism in foam cell. These data appear to support the SAMD1/LDL retention hypothesis of lesion growth. Despite apparently irreversible binding of human LDL to full-length human SAMD1, efficient anti-SAMD1-antibody inhibitors were created. In vivo lesion targeting of inhibitors was demonstrated by MRI, ultrasound, and ex vivo microscopy. However, only non-statistically significant reductions in spontaneous lesion size in apoE-/- mice were seen after 12 weeks of treatment with PEG-fab inhibitors of SAMD1/LDL binding. In contrast, these inhibitors substantially reduced LDL retention in carotid injury lesions in apoE-/- and LDLR-/- mice 7 days after injury. The most obvious difference between injury lesions and early spontaneous lesions is the presence of numerous smooth muscle cells and associated extracellular matrix in the injury lesions. Thus, SAMD1 may be involved in retention of apoB-Lps in mouse lesions, but not until smooth muscle cells have entered the intima. In addition, SAMD1 is seen throughout arteries in changing patterns that suggest broader and more complicated roles in atherosclerosis.
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Peer review report
Reviewer: GE Rainger Institution: University of Birmingham, UK email: g.e.rainger@bham.ac.uk
General comments
The English is generally acceptable, but there are serious lapses of syntax throughout the manuscript that require revision.
Some sections, e.g. the introduction revert to a bullet pointed format for conveying information from specific citations. If the authors choose to submit to a journal, this is not acceptable in many journal formats.
Figures are not publication quality and do not conform to a standard format. They often show images of single cells or sections as evidence of complex biology which needs formalising into graphs which show outcomes of the analysis of multiple experiments.
As far as I can see there is no statistical analysis of any of the data (at least as presented in the figures), it is …
Peer review report
Reviewer: GE Rainger Institution: University of Birmingham, UK email: g.e.rainger@bham.ac.uk
General comments
The English is generally acceptable, but there are serious lapses of syntax throughout the manuscript that require revision.
Some sections, e.g. the introduction revert to a bullet pointed format for conveying information from specific citations. If the authors choose to submit to a journal, this is not acceptable in many journal formats.
Figures are not publication quality and do not conform to a standard format. They often show images of single cells or sections as evidence of complex biology which needs formalising into graphs which show outcomes of the analysis of multiple experiments.
As far as I can see there is no statistical analysis of any of the data (at least as presented in the figures), it is unclear what statistical analysis has been conducted when the text states that significant effects have been observed.
It is not clear how reproducible assays such as the in vitro EC injury model are and this sort of concern would need addressing.
The discussion is unfocused. Having read the full manuscript I am not informed about what SAMD1 is, how it achieves extracellular distribution, how it functions in the localisation of LDL and formation of foam cells etc. There are many broad brush strokes here, but there is not enough mechanistic detail to provide convincing arguments for its functions as extrapolated by the authors.
Section 1 – Serious concerns
Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? No
Requires revisions: No details of ethics and the manuscript contains objective errors that must be addressed
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Peer review report
Reviewer: Yaw Asare Institution: ISD LMU email: yaw.asare@med.uni-muenchen.de
General comments
The current manuscript is very diffuse with many figures that should be merged to one main figure with a clear message. The reader is easily lost going through multiple figure panels conveying pieces of information. The manuscript will further benefit from reducing the length of the discussion.
Section 1 – Serious concerns
- Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
- Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable
Section 2 – Language quality
- How would you rate the English language quality? High quality
Section 3 – validity and reproducibility
- Does the work cite relevant and …
Peer review report
Reviewer: Yaw Asare Institution: ISD LMU email: yaw.asare@med.uni-muenchen.de
General comments
The current manuscript is very diffuse with many figures that should be merged to one main figure with a clear message. The reader is easily lost going through multiple figure panels conveying pieces of information. The manuscript will further benefit from reducing the length of the discussion.
Section 1 – Serious concerns
- Do you have any serious concerns about the manuscript such as fraud, plagiarism, unethical or unsafe practices? No
- Have authors’ provided the necessary ethics approval (from authors’ institution or an ethics committee)? not applicable
Section 2 – Language quality
- How would you rate the English language quality? High quality
Section 3 – validity and reproducibility
- Does the work cite relevant and sufficient literature? Yes
- Is the study design appropriate and are the methods used valid? Yes
- Are the methods documented and analysis provided so that the study can be replicated? Yes
- Is the source data that underlies the result available so that the study can be replicated? Yes
- Is the statistical analysis and its interpretation appropriate? Yes
- Is quality of the figures and tables satisfactory? No
- Are the conclusions adequately supported by the results? No
Section 4 – Suggestions
- In your opinion how could the author improve the study?
The manuscript will further benefit from the following experiments:
Assessing the effect of targeting SAMD1/LDL axis in neointima formation following arterial injury given the reduced LDL retention in injured carotids.
Analyzing effects of PEG-fab inhibitors in early lesions induced by atherogenic diet.
- Describing the role of SAMD1 in VSMC foam cell formation.
Section 5 – Decision
Requires revisions: The manuscript contains objective errors that must be addressed
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