Mechanical Regulation of Protein Translation in the Cardiovascular System

Abstract

The cardiovascular system can sense and adapt to changes in mechanical stimuli by remodeling the physical properties of the heart and blood vessels in order to maintain homeostasis. Imbalances in mechanical forces and/or impaired sensing are now not only implicated but are, in some cases, considered to be drivers for the development and progression of cardiovascular disease. There is now growing evidence to highlight the role of mechanical forces in the regulation of protein translation pathways. The canonical mechanism of protein synthesis typically involves transcription and translation. Protein translation occurs globally throughout the cell to maintain general function but localized protein synthesis allows for precise spatiotemporal control of protein translation. This Review will cover studies on the role of biomechanical stress -induced translational control in the heart (often in the context of physiological and pathological hypertrophy). We will also discuss the much less studied effects of mechanical forces in regulating protein translation in the vasculature. Understanding how the mechanical environment influences protein translational mechanisms in the cardiovascular system, will help to inform disease pathogenesis and potential areas of therapeutic intervention.

Keywords: cardiac; endothelial; mechanotransduction; pressure overload; protein translation; shear stress.

FIGURE 1

Schematic representation of mTOR signaling. In response to mechanical force, PI3K activates Akt and mTORC2 directly. mTORC2 can further activate Akt which can also directly activate mTORC1. Rheb can directly activate mTORC1 when in its active GTP bound form. Activation of mTORC1 positively regulates S6K1/p70S6K leading to downstream ribosome and mRNA biogenesis. In addition, activation of mTORC1 also negatively regulates 4EBP1 allowing for the formation of the eIF4F translation initiation complex. This combined signaling promotes protein synthesis and cell growth. When mTORC2 is activated it also promotes cell growth and survival through its downstream effectors SGK1 and PKCα. Adaptor proteins, Raptor and Rictor, are specific to mTORC1 and mTORC2, respectively, and are required for active signal transduction. The TSC1/2 complex can prevent mTORC1 activation by Rheb by keeping Rheb in its inactive GDP form. The TSC1/2 complex can be activated by both AMPK and GSK3β signaling to dampen mTORC1 activity in times of cellular stress. GSK3β can also inhibit eIF2α mediated protein translation again to reduce global protein synthesis during cellular stress. In addition, there are four kinases which can phosphorylate and inactivate eIF2α mediated protein translation under distinct stress conditions: PERK, GCN2, PKR and HRI. Phosphoinositide-3-kinase–protein kinase B/Akt (PI3K-PKB/Akt), Mammalian target of rapamycin (mTOR), Tuberous sclerosis protein (TSC), 5′ adenosine monophosphate-activated protein kinase (AMPK), Glycogen synthase kinase 3β (GSK3β), Ras homolog enriched in brain (Rheb), Eukaryotic initiation factor 2α (eIF2α), Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), General control non-derepressible 2 (GCN2), Protein kinase RNA-activated (PKR), Heme-regulated inhibitor kinase (HRI), Ribosomal protein S6 kinase beta-1 (S6K1) or p70S6 kinase (p70S6K), Eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1), Serine/threonine-protein kinase Sgk1 also known as serum and glucocorticoid-regulated kinase 1 (SGK1), Protein kinase C alpha (PKCα).

FIGURE 2

Cellular ER Stress signaling in response to mechanical force. Increased protein synthesis results from chronic mechanical activation of pathways such as mTOR. This results in an increase in protein burden, accumulation of misfolded proteins and ER stress. In an attempt to re-establish ER homeostasis, the UPR is triggered and this consists of three main branches. The eIF2α kinase PERK is an ER transmembrane protein which acts as a sensor to increased protein load and accumulation of unfolded proteins in the ER. Once stimulated, PERK will phosphorylate eIF2α and thereby block global translation initiation to help reduce protein burden in the ER. Phosphorylation of eIF2α also leads to translation of a specific subset of mRNA which will help maintain cellular function and promote cell survival during stress conditions. In times of ER stress, ATF6 will translocate from the ER to the Golgi where it will become cleaved and function as an active transcription factor, promoting the transcription of ER chaperones. IRE1catalyses the splicing of key mRNAs that will become functional transcriptions factors and similar to ATF6, these will promote the transcription and ultimate translation of ER chaperones which will facilitate proper protein folding and degradation to alleviate ER burden. Endoplasmic reticulum (ER), Mammalian target of rapamycin (mTOR), Unfolded protein response (UPR), Eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), Activating transcription factor 6 (ATF6), Serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), Eukaryotic initiation factor 2α (eIF2α).