Blocking Extracellular Chaperones to Improve Cardiac Regeneration.

Laura Seclì,Matteo Sorge,Mara Brancaccio,Alessandro Morotti

doi:10.3389/fbioe.2020.00411

Abstract

Chronic or acute insults to the myocardium are responsible for the onset of cardiomyopathy and heart failure. Due to the poor regenerative ability of the human adult heart, the survival of cardiomyocytes is a prerequisite to support heart function. Chaperone proteins, by regulating sarcomeric protein folding, function, and turnover in the challenging environment of the beating heart, play a fundamental role in myocardial physiology. Nevertheless, a number of evidences indicate that, under stress conditions or during cell damage, myocardial cells release chaperone proteins that, from the extracellular milieu, play a detrimental function, by perpetuating inflammation and inducing cardiomyocyte apoptosis. Blocking the activity of extracellular chaperones has been proven to have beneficial effects on heart function in preclinical models of myocardial infarction and cardiomyopathy. The application of this approach in combination with tissue engineering strategies may represent a future innovation in cardiac regenerative medicine.

Highlights

Specialty section: This article was submitted to Biomaterials, a section of the journal Frontiers in Bioengineering and Biotechnology
The family of small heat shock proteins (sHSPs) is characterized by the absence of ATPase activity, a lower molecular weight, the presence of a highly conserved α-crystallin domain, and their attitude to form oligomers (Carra et al, 2019; Haslbeck et al, 2019). Both ATP-dependent chaperones and sHSPs play a protective role in the myocardium thanks to their ability to cope with protein misfolding, to promote unfolded protein degradation and to support survival signaling in cardiomyocytes (Willis and Patterson, 2013; Tarone and Brancaccio, 2014)
Treatment with recombinant HSP27 activates an inflammatory response in human and murine coronary vascular endothelial cells, promoting the overexpression of ICAM-1, MCP-1, IL-6, and IL-8 in a dose-dependent manner. All these effects are mediated by Toll-like receptor 2 (TLR2) and 4, since the treatment with HSP27 has no effect on cells derived from TLR2-null or

Summary

Blocking Extracellular Chaperones to Improve Cardiac Regeneration

Specialty section: This article was submitted to Biomaterials, a section of the journal Frontiers in Bioengineering and Biotechnology. By regulating sarcomeric protein folding, function, and turnover in the challenging environment of the beating heart, play a fundamental role in myocardial physiology. A number of evidences indicate that, under stress conditions or during cell damage, myocardial cells release chaperone proteins that, from the extracellular milieu, play a detrimental function, by perpetuating inflammation and inducing cardiomyocyte apoptosis. Blocking the activity of extracellular chaperones has been proven to have beneficial effects on heart function in preclinical models of myocardial infarction and cardiomyopathy. The application of this approach in combination with tissue engineering strategies may represent a future innovation in cardiac regenerative medicine

INTRACELLULAR CHAPERONES

CONCLUSION