Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease

Zhang, Guangyu; Wang, Xiaoding; Gillette, Thomas G.; Deng, Yingfeng; Wang, Zhao V.

doi:10.2174/1568026619666190521093049

Cited by 33 publications

(21 citation statements)

References 172 publications

(68 reference statements)

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“…These mice also show an increase in cardiac fibrosis with increased expression of fibrotic (periostin) and ER stress (PERK) proteins. Increased PERK expression indicates activation of the unfolded protein response (UPR) and ER stress, which has been shown to be induced in multiple forms of CVD and is increased in failing human hearts (37,90). Consistent with these results, RNA-seq analysis also shows a broad increase in hypertrophic, fibrotic, and inflammatory marker genes in these hearts confirming pathological hypertrophy and fibrosis.…”

Section: Discussionsupporting

confidence: 54%

Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis

Guarnieri

Anthony

Gozdiff

et al. 2021

Preprint

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Adipose tissue continues to gain appreciation for its broad role as an endocrine organ, and disruptions in adipose tissue homeostasis plays a central role in cardiovascular physiology. We have previously shown that expression of the RNA binding protein HuR in adipose tissue mediates energy expenditure, but the potential cardiovascular impacts of this finding have not been explored. We show here that adipose tissue-specific deletion of HuR (Adipo-HuR-/-) is sufficient to induce the spontaneous development of cardiac hypertrophy and fibrosis. Hearts from Adipo-HuR-/- mice have increased left ventricular (LV) ejection fraction, rate of pressure generation, and LV posterior wall thickness that is accompanied by an increase in LV/body weight ratio and hypertrophic gene expression. Furthermore, Adipo-HuR-/- hearts display increased fibrosis by picrosirius red staining and periostin expression. To identify underlying mechanisms, we applied both RNA-seq and weighted gene co-expression network analysis (WGCNA) to define HuR-dependent changes in gene expression as well as significant relationships between adipose tissue gene expression and LV mass. RNA-seq results demonstrate a significant increase in pro-inflammatory gene expression in the subcutaneous white adipose tissue (scWAT) from Adipo-HuR-/- mice that is accompanied by an increase in serum levels of both TNF-α and IL-6. WGCNA identified a significant enrichment in inflammation, apoptosis/cell death, and vesicle-mediated transport genes among those whose expression most significantly associated with CVD in Adipo-HuR-/-. In conclusion, we demonstrate that the loss of HuR expression in adipose tissue promotes the development of cardiac hypertrophy and fibrosis, potentially through modulation of inflammation and vesicle-mediated transport in scWAT.NEW AND NOTEWORTHYThis work demonstrates the spontaneous development of cardiac hypertrophy and fibrosis upon adipose tissue-specific deletion of the RNA binding protein HuR that appears to be mechanistically driven by HuR-dependent changes in inflammatory and extracellular vesicle transport mediating genes in the subcutaneous white adipose tissue. These results suggest that loss of HuR expression in adipose tissue in obesity, as demonstrated in mouse and humans by our group and others, may contribute to obesity-mediated CVD.

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Section: Discussionsupporting

confidence: 54%

Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis

Guarnieri

Anthony

Gozdiff

et al. 2021

Preprint

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“…There are several important proteins that are activated by ERS, including ATF6, Xbp1, ATF4, CHOP and IRE1. ATF6 normally functions in the adaptive UPR to accelerate the remodeling of cellular physiology and recovery following acute physiological and pathological injury ( 146 ). ATF6 can dimerize with UPR-regulated basic leucine zipper transcription factors, such as Xbp1, by S1P/S2P-dependent proteolysis, or associate with other stress-responsive signaling pathways such as mTOR signaling ( 147 , 148 ).…”

Section: Upr In Turn Mediates I/r Damagementioning

confidence: 99%

Endoplasmic reticulum stress serves an important role in cardiac ischemia/reperfusion injury (Review)

et al. 2020

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Although acute myocardial infarction is one of the most common fatal diseases worldwide, the understanding of its underlying pathogenesis continues to develop. Myocardial ischemia/reperfusion (I/R) can restore myocardial oxygen and nutrient supply. However, a large number of studies have demonstrated that recovery of blood perfusion after acute ischemia causes reperfusion injury to the heart. With progress made in the understanding of the underlying mechanisms of myocardial I/R and oxidative stress, a novel area of research that merits greater study has been identified, that of I/R-induced endoplasmic reticulum (ER) stress (ERS). Cardiac I/R can alter the function of the ER, leading to the accumulation of unfolded/misfolded proteins. The resulting ERS then induces the activation of signal transduction pathways, which in turn contribute to the development of I/R injury. The mechanism of I/R injury, and the causal relationship between I/R and ERS are reviewed in the present article.

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“…However, chronic ER stress sustains UPR, which is associated with a heightened inflammatory response in multiple CVD models including those with AngII infusion [11,[14][15][16]. Accordingly, interventions on ER proteostasis have been identified as promising therapeutics [17][18][19].…”

Section: Introductionmentioning

confidence: 99%

78 kDa Glucose-Regulated Protein Attenuates Protein Aggregation and Monocyte Adhesion Induced by Angiotensin II in Vascular Cells

Cicalese

Okuno

Elliott

et al. 2020

IJMS

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Investigations of vascular smooth muscle cell (VSMC) phenotypic modulation due to angiotensin II (AngII) stimulation are important for understanding molecular mechanisms contributing to hypertension and associated vascular pathology. AngII induces endoplasmic reticulum (ER) stress in VSMCs, which has been implicated in hypertensive vascular remodeling. Under ER stress, 78 kDa glucose-regulated protein (GRP78) acts as an endogenous chaperone, as well as a master controller of unfolded protein response (UPR) to maintain protein quality control. However, the potential downstream consequences of ER stress induced by AngII on protein quality control and pro-inflammatory phenotype in VSMCs remain elusive. This study aims to identify protein aggregation as evidence of the disruption of protein quality control in VSMCs, and to test the hypothesis that preservation of proteostasis by overexpression of GRP78 can attenuate the AngII-induced pro-inflammatory phenotype in VSMCs. Increases in protein aggregation and enhanced UPR were observed in VSMCs exposed to AngII, which were mitigated by overexpression of GRP78. Moreover, GRP78 overexpression attenuated enhanced monocyte adhesion to VSMCs induced by AngII. Our results thus indicate that the prevention of protein aggregation can potentially mitigate an inflammatory phenotype in VSMCs, which may suggest an alternative therapy for the treatment of AngII-associated vascular disorders.

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Unfolded Protein Response as a Therapeutic Target in Cardiovascular Disease

Cited by 33 publications

References 172 publications

Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis

Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis

Endoplasmic reticulum stress serves an important role in cardiac ischemia/reperfusion injury (Review)

78 kDa Glucose-Regulated Protein Attenuates Protein Aggregation and Monocyte Adhesion Induced by Angiotensin II in Vascular Cells

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