The Role of the Piezo1 Mechanosensitive Channel in Heart Failure
Round 1
Reviewer 1 Report
Yuan et al. reviewed the role of Piezo1 in heart failures in cell type specific manner. The review could be useful to the researchers in the field by updating new references. I saw several points that could potentially help the manuscript.
1. Authors need to provide a section describing Piezo1 KO mouse phenotypes related to heart failure.
2. Figure 1 is not matching very well with its legend and busy to follow. I would try to lay out four separate figures representing each Piezo1 functions.
3. In page3, line 117, shear flow needs to be changed to shear stress.
4. 2.1 Piezo1 structure section is hard to be understood and needs to be supplemented with a structure figure otherwise can be removed entirely.
5. Extensive English editing would be useful.
needs extensive English editing
Author Response
- Authors need to provide a section describing Piezo1 KO mouse phenotypes related to heart failure.
Response 1: A description of the Piezo1 KO mouse phenotype associated with heart failure has been added in section 3.1.2. The additions include “Jiang et al. found that Piezo1 channel mediates the stretch-induced Ca2+ response of CMs, which in turn produces ROS. The study revealed moderate enlargement of the left ventricle in the hearts of KO-piezo1 mice, markedly enhanced interstitial fibrosis in heart slices, and reduced ejection fraction.”
- Figure 1 is not matching very well with its legend and busy to follow. I would try to lay out four separate figures representing each Piezo1 functions.
Response 2: We have split the previous Figure1 into Figure2, Figure3, Figure4, and Figure5 in the article.
- In page3, line 117, shear flow needs to be changed to shear stress.
Response 3: Yes, we have changed the shear flow to shear stress in page 3, line 117.
- 2.1 Piezo1 structure section is hard to be understood and needs to be supplemented with a structure figure otherwise can be removed entirely.
Response 4: We have added a simple diagram of the piezo1 structure in Figure 1 in the article.
Reviewer 2 Report
Comments:
Abstract:
- The sentence "One of these pathways is that of drug development, which … ultrasound genetic remote modulation" is quite long and could be split into two or more sentences for clarity. For example, it might be clearer to separately discuss drug development and ultrasound genetic remote modulation as two different strategies to modulate Piezo1.
- The reference to 'drug development' seems unclear. Are the authors suggesting that the mentioned compounds (GsMTx4, Yoda1, Jedi1, Jedi2) are being developed as drugs, or are they tools for studying Piezo1?
- The abstract should provide a definitive conclusion or potential implications for the research. The authors mention that these strategies provide a "new direction for HF therapy," but it would be beneficial to have a more definitive statement regarding the potential benefits and the implications for future research.
- It would also be beneficial to include a sentence about the gap in current research that this review is addressing. Is there a particular novelty in your approach or findings?
Introduction:
- The description of Heart Failure currently lacks the requisite scientific detail expected in an academic review. It would be helpful to include a more comprehensive definition of HF, along with clear discussion on its etiology and categorization.
- The phrase "HF is categorized into three types based on the location of the defect " could benefit from rephrasing for clarity.
- The section discussing the role of various cell types in heart failure appears to be somewhat unorganized. You might consider reordering this content in a way that presents a more logical flow of ideas.
- Some sentences in the introduction are relatively lengthy, which might hinder readability. Try splitting these into shorter, more straightforward sentences. This would likely enhance the overall clarity and accessibility of your text, making it easier for readers to follow and understand your argument.
- The introduction could be improved by establishing a clearer context for the importance of Piezo1 in the field of cellular biology, especially in relation to cardiac health. Explaining why Piezo1 is a topic of interest would help to motivate the review and engage readers.
Piezo1 activation mechanism:
- The hypothesis regarding the changes in membrane tension leading to the activation of the Piezo1 channels is not adequately supported. More references or deeper discussion into these proposed mechanisms would strengthen this section.
The Necessity for Piezo1 in HF:
- The section about chemokines could be expanded upon to provide a more comprehensive view of their role in the pathogenesis of HF.
- The statement about the lymphatic vessels' role in fluid and immune cell tissue clearance is interesting, but it might be beneficial to provide more details or context about this process and its implications in HF.
Cardiac Structural Cells:
- For CFs, it might be beneficial to further delve into the potential therapeutic implications of modulating Piezo1 expression and activation in the progression of myocardial fibrosis and heart failure.
- In the CMs section, more information could be added on how Piezo1's roles might differ between physiological and pathological conditions. This could help better understand its significance in cardiomyopathy and arrhythmias.
- For ECs, more detail about the connection between Piezo1 and atherosclerosis would add depth to this section. Also, it might be beneficial to explain the importance of shear stress in vascular endothelial cells.
- Would be helpful to ensure that all abbreviations are defined before use.
T Cells:
- While the authors have discussed the roles of T-cell subsets in HF, they could clarify their mechanisms of action further. How do these subsets differentially contribute to the development of HF? What are the implications of these differences for therapeutic strategies?
Potential Applications of Piezo1 Research:
- A brief discussion on potential strategies to chemically modify compounds like Yoda1 to enhance apoptosis in certain types of cells could offer greater insight into the development of more effective drugs.
- While ultrasound-based modulation of Piezo1 is presented as a promising therapeutic direction, it would be important to highlight potential challenges or limitations of this approach, including potential off-target effects, safety concerns, and the current state of the technology.
Conclusion section:
- A typo is present in the section header "Concussion," which should be corrected accordingly.
- The conclusion could begin with a restatement of the purpose of the review and a summary of the main findings. This can serve as a reminder of the objective and provide a clearer context for the concluding remarks.
- While the authors hint at the importance of further studies in this field, more explicit commentary on future research directions would enhance this section. Discussing potential obstacles and how they might be overcome could provide valuable insight.
Moderate editing of English language required
Author Response
Please see the attachment.
Author Response File: 
Author Response.pdf
Round 2
Reviewer 1 Report
The manuscript has been significantly improved and looks appropriate for publication.
Reviewer 2 Report
I would like to thank the authors for revising this manuscript and satisfactorily responding to the reviewers' comments.
Minor editing of English language required
