Journal
EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
Volume 51, Issue 5, Pages -Publisher
WILEY
DOI: 10.1111/eci.13504
Keywords
amyloid; cardiovascular diseases; oligomer; protein misfolding; therapy; unfolded protein responses
Funding
- Forschungskredit University of Zurich [FK-19-043]
- National Institutes of Health [3R01HL118067-07S1, R01AG057046, R01HL156116]
- American Heart Association [17CSA33620007, 20SRG35540029]
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This review discusses the recent progress in understanding protein misfolding and compromised protein quality control in cardiovascular diseases, highlighting the lack of successful translation from preclinical models to clinical settings. More collaboration between basic scientists and clinicians is needed to develop specific biomarkers and therapeutic strategies to target proteotoxicity in CVD patients.
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.
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