Oral geranylgeranylacetone treatment increases heat shock protein expression in human atrial tissue

Marion, Denise M. S. van; Dorsch, Larissa M.; Hoogstra-Berends, Femke; Kakuchaya, T.T.; Bockeriа, L.A.; Groot, Natasja M.S. de; Brundel, Bianca J. J. M.

doi:10.1016/j.hrthm.2019.07.010

Cited by 16 publications

(11 citation statements)

References 33 publications

(77 reference statements)

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“…(d) To maintain good quality protein in the body, heat shock proteins (HSPs) are vital. Geranylgeranylacetone (GGA) induces heat shock protein (Hsp70) in mammalian tissues and promotes insulin sensitivity in old mice (Silverstein et al, 2015), while van Marion et al (2020) showed that it increases HSP expression in atrial tissue after heart surgery. Pride et al (2015) showed that long‐lived species, compared with related short‐lived species within the same order, have elevated HSP levels in conjunction with better proteostasis.…”

Section: Introductionmentioning

confidence: 99%

17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex

et al. 2021

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Section: Introductionmentioning

confidence: 99%

17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex

et al. 2021

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“…Treatment with GGA resulted in higher levels of HSP70 and other small HSPs in the myofilament fractions of right and left atrial appendage tissue. This could indicate that GGA treatment results in the upregulation of beneficial HSPs that could potentially attenuate IRI following MI ( 83 ). Importantly, both bimoclomol and GGA are indirect regulators of HSP70 and these studies fail to establish a clear causal role between upregulation of HSP70 and the observed treatment effects.…”

Section: Damage-associated Molecular Patterns Related To Myocardial Imentioning

confidence: 99%

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

et al. 2020

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In the setting of myocardial infarction (MI), ischemia reperfusion injury (IRI) occurs due to occlusion (ischemia) and subsequent re-establishment of blood flow (reperfusion) of a coronary artery. A similar phenomenon is observed in heart transplantation (HTx) when, after cold storage, the donor heart is connected to the recipient’s circulation. Although reperfusion is essential for the survival of cardiomyocytes, it paradoxically leads to additional myocardial damage in experimental MI and HTx models. Damage (or danger)-associated molecular patterns (DAMPs) are endogenous molecules released after cellular damage or stress such as myocardial IRI. DAMPs activate pattern recognition receptors (PRRs), and set in motion a complex signaling cascade resulting in the release of cytokines and a profound inflammatory reaction. This inflammatory response is thought to function as a double-edged sword. Although it enables removal of cell debris and promotes wound healing, DAMP mediated signalling can also exacerbate the inflammatory state in a disproportional matter, thereby leading to additional tissue damage. Upon MI, this leads to expansion of the infarcted area and deterioration of cardiac function in preclinical models. Eventually this culminates in adverse myocardial remodeling; a process that leads to increased myocardial fibrosis, gradual further loss of cardiomyocytes, left ventricular dilation and heart failure. Upon HTx, DAMPs aggravate ischemic damage, which results in more pronounced reperfusion injury that impacts cardiac function and increases the occurrence of primary graft dysfunction and graft rejection via cytokine release, cardiac edema, enhanced myocardial/endothelial damage and allograft fibrosis. Therapies targeting DAMPs or PRRs have predominantly been investigated in experimental models and are potentially cardioprotective. To date, however, none of these interventions have reached the clinical arena. In this review we summarize the current evidence of involvement of DAMPs and PRRs in the inflammatory response after MI and HTx. Furthermore, we will discuss various current therapeutic approaches targeting this complex interplay and provide possible reasons why clinical translation still fails.

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“…In AF patients, the oral administration of geranylgeranylacetone (GGA) is associated with increased expression of HSPs in atrial tissue, suggesting the potential effect of GGA in limiting misfolded protein-mediated damage. 92 In preclinical studies, the cardioprotective role of GGA has been tested in cardiomyocytes from rodents models of cardiac diseases, where GCA induces the expression of HSPs through the activation of heat shock factor-1, resulting in decreased oligomer and aggregate formation, improved cardiac function and survival. [93][94][95] Another class of HSPs modulator with cardioprotective effects is celastrol, also a heat shock transcription factor 1 inducer.…”

Section: Molecular Chaperonesmentioning

confidence: 99%

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

Diteepeng

Monte

Luciani

2021

Eur J Clin Investigation

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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.

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Oral geranylgeranylacetone treatment increases heat shock protein expression in human atrial tissue

Cited by 16 publications

References 33 publications

17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex

17‐a‐estradiol late in life extends lifespan in aging UM‐HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex

Damage-Associated Molecular Patterns in Myocardial Infarction and Heart Transplantation: The Road to Translational Success

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

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