The Role and Molecular Mechanism of P2Y12 Receptors in the Pathogenesis of Atherosclerotic Cardiovascular Diseases

Round 1

Reviewer 1 Report

The authors describe a very interesting review of molecular mechanism of P2Y1 receptors in the pathogenesis of thrombosis, fluid shear stress, and atherosclerosis. The P2Y12 receptor, which plays a central role in platelet activation and in thrombus growth and stabilization, is an established target for antithrombotic drugs such as the thienopyridines clopidogrel or prasugrel, or direct reversible antagonists such as ticagrelor or cangrelor.

The manuscript is well structured, but some parts are missing some important facts that authors should add.

Page 2, lines: 78-91: The authors describe platelet adhesion, but the manuscript lacks an important part of platelet adhesion: the von Willebrand factor (vWF). VWF represents a high-molecular-weight adhesive glycoprotein that plays an essential role in primary hemostasis by promoting platelet adhesion to the subendothelium and platelet plug formation at the sites of vascular injury.

Page 2, lines: 82-88: The authors should, in addition to the listed causes of arterial thrombosis in platelet dysfunction. It is described in the literature as congenital thrombocytopathy leading to thrombosis - sticky platelet syndrome (SPS). It has been suggested that the defects of the platelet membrane glycoproteins or intracellular signal pathways involved in platelet activation and aggregation are responsible for the disorder. Authors should cite the manuscript in which it was described: Clin Appl Thromb Hemost. 2018 Oct;24(7):1027-1032. doi: 10.1177/1076029618779136. 

Page 3, lines 116-119: In this section, the authors should add the following statement. ,,These interactions are facilitated by the release of the intracellular tether of GP IIb/IIIa, possibly via release from cytoskeletal actin components (the so-called inside-out signaling), which allows the extracellular domains of the GP IIb/IIIa receptor complex to expose multiple binding sites for fibrinogen and, also, for the von Willebrand factor." Therefore, it is very important to quote this manuscript: Int J Mol Sci. 2020 Jun 29;21(13):4616. doi: 10.3390/ijms21134616.

The figure in the text is very clearly written.

Table 1 the table is very confusing, it needs to be adjusted.

I have to say that with these 68 references less than half of the references are in the last 5 years. It is appropriate to add new references.

Author Response

Please see the response on the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

In the paper “The role and molecular mechanism of P2Y1 receptors in the pathogenesis of atherosclerotic cardiovascular diseases”, the authors have summarized the evidence about P2Y receptors in atherosclerosis progression. The topic of the manuscript is certainly interesting and captures one of the questions on the pathophysiology of cardiovascular disease.

The manuscript is well written, however, there are some points to clarify:

• The authors refer to the P2Y1 receptor in the title. In the text, after an initial overview of all receptors in the family, the authors focus on the P2Y12 receptor.  Please clarify this point or change the title.
• Please make Table 1 more readable and understandable. The "Functions" row does not have exact matches to the rows. The table is confusing.  
• It specifies that ticagrelor is approved in 2 different dosages 90 and 60 mg, citing the following references: N Engl J Med 2015; 372:1791-1800
  DOI: 10.1056/NEJMoa1500857; J Cardiovasc Pharmacol. 2020 Aug;76(2):173-180. doi: 10.1097/FJC.0000000000000856.
• Please, you should explain each of your abbreviations the first time it appears in the main text (i.e. ACS).

Author Response

Please see the response in the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

The presented manuscript has been corrected in response to the suggestions. The authors have followed the recommendations of the reviewer. After the revision, the provided data and addition of the results became more clear. I would like to thank the authors for resubmitting the manuscript and explaining the obscure points from the previous version.