Designing Novel Therapies to Mend Broken Hearts: ATF6 and Cardiac Proteostasis

Round 1

Reviewer 1 Report

The authors wrote an excellent review article on an interesting topic that is not widely known to all cardiology researchers.

They describe the role of an activating transcription factor (ATF6) in both physiological and pathological cardiac hypertrophy as a regulator of protein folding, and they explain the fine underlying signaling pathways that relate ATF6 to the proteostasis process. The involvement of ATF6 in other pathologies, such as myocardial infarction, is also discussed.

This review article is comprehensive, well written and does not require any revision.

Reviewer 2 Report

In this review article, the authors focused on the unfolded protein response regulatory transcription factor ATF6 and the role of proteostasis in cardiac pathophysiology. As authors highlighted, cardiac diseases are still a major health concern worldwide. Recent studies suggest that the imbalance in protein quality control plays a crucial role in the onset of multiple cardiac pathologies. Proteostasis is maintained by various signaling events that coordinate protein synthesis and folding with the degradation of misfolded, potentially toxic proteins. Proteostasis imbalance leads to the metabolic catastrophe in the heart and, ultimately, heart failure. In the current review article, authors have covered various aspects of the ATF6 and proteostasis in cardiac pathophysiology, specifically the role of ATF6 in terms of cardiac hypertrophy. Authors comprehensively covered the molecular events associated with the activation of ATF6 and proteostasis, ATF6 in hypertrophy, CHD, MI, hemodynamic balance, gene programming, and discussed the small molecules targeting ATF6 for therapeutic purposes. This is an exciting and timely review article. The manuscript is very well written and presented in a logical manner.