The long and winding road to target protein misfolding in cardiovascular diseases

Abstract

Background: In the last decades, cardiovascular diseases (CVD) have remained the first leading cause of mortality and morbidity in the world. Although several therapeutic approaches have been introduced in the past, the development of novel treatments remains an important research goal, which is hampered by the lack of understanding of key mechanisms and targets. Emerging evidences in recent years indicate the involvement of misfolded proteins aggregation and the derailment of protein quality control in the pathogenesis of cardiovascular diseases. Several potential interventions targeting protein quality control have been translated from the bench to the bedside to effectively employ the misfolded proteins as promising therapeutic targets for cardiac diseases, but with trivial results. Design: In this review, we describe the recent progresses in preclinical and clinical studies of protein misfolding and compromised protein quality control by selecting and reporting studies focusing on cardiovascular diseases including cardiomyopathies, cardiac amyloidosis, atherosclerosis, atrial fibrillation and thrombosis. Results: In preclinical models, modulators of several molecular targets (eg heat shock proteins, unfolded protein response, ubiquitin protein system, autophagy and histone deacetylases) have been tested in various conditions with promising results although lacking an adequate transition towards clinical setting. Conclusions: At present, no therapeutic strategies have been reported to attenuate proteotoxicity in patients with CVD due to a lack of specific biomarkers for pinpointing upstream events in protein folding defects at a subclinical stage of the diseases requiring an intensive collaboration between basic scientists and clinicians. K E Y W O R D Samyloid, cardiovascular diseases, oligomer, protein misfolding, therapy, unfolded protein responses 2 of 17 | DITEEPENG ET al.

Thermophiles reveal the clues to longevity: precise protein synthesis

“…While the authors propose that it is essential for translational accuracy, they note that the mutation may alter the structure of the ribosomal RNA, resulting in a conformational transition of the 30/40S ribosome, which may lead to translational accuracy. It is worth noting that both lysine and arginine are positively charged basic amino acids that take part in electrostatic interactions [14] . However, the guanidinium group in arginine permits interactions at more than one orientation, thereby allowing for a greater number of electrostatic connections than lysine [14] .…”

“…It is worth noting that both lysine and arginine are positively charged basic amino acids that take part in electrostatic interactions [14] . However, the guanidinium group in arginine permits interactions at more than one orientation, thereby allowing for a greater number of electrostatic connections than lysine [14] . Exact biochemical and structural information is now awaited to test this hypothesis.…”

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“…Accordingly, the protein molecules 'stick' with each other. Protein aggregation may also be a consequence of protein hyperphosphorylation, self-catalytic conformational conversion, or genetic mutations leading to an unstable protein [3][4][5][6][7][8].…”

Sarcostat mechanism: A promising therapeutic strategy for misfolded proteins in cardiomyopathy

“…3 Taken together, therapeutic strategies that restore the protein folding capacity and attenuate cardiac proteotoxicity begin to be considered as novel approaches to cardiomyopathy, such as stabilization of protein folding, clearance of misfolded proteins and enhancement of PQC. 1,8 Whether the sarcostat mechanism can be widely accepted and considered as promising therapeutic strategies is still not completely clear and needs further study.…”

“…To the Editor, It was with great interest that we read the study entitled "The long and winding road to target protein misfolding in cardiovascular diseases" by Thamonwan Diteepeng and colleagues published in The Journal of The European Journal of Clinical Investigation in May 2021. 1 In this interesting paper, the authors describe the recent progresses in preclinical and clinical studies of protein misfolding and compromised protein quality control (PQC) by selecting and reporting studies focusing on cardiovascular diseases including cardiomyopathies, cardiac amyloidosis, atherosclerosis, atrial fibrillation and thrombosis. 1 Many researchers were consistent with the author and revealed misfolding of proteins and impaired PQC leads to cardiac proteotoxicity, contributing to the initiation, progression and development of cardiomyopathy.…”