Impaired cardiac mitochondrial oxidative phosphorylation and enhanced mitochondrial oxidative stress in feline hypertrophic cardiomyopathy

Christiansen, Leif; Dela, Flemming; Koch, J.; Hansen, Christina; Leifsson, Páll S.; Yokota, Takashi

doi:10.1152/ajpheart.00727.2014

Cited by 48 publications

(58 citation statements)

References 55 publications

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“…Elevated expression of the ER stress markers GRP78, eIF2α, and XBP1 and increased activation of the UPR ER is observed in patients with the p.S143P mutation in the intermediate filament gene lamin A/C, the most frequently reported genetic variant in inherited dilated cardiomyopathy (DCM) [82]. Enhanced mitochondrial oxidative stress and mitochondrial dysfunction were observed in the heart of cats with hypertrophic cardiomyopathy (HCM) [83]. Moreover, impaired autophagy was shown in a Mybpc3-targeted knockin HCM mouse model and in DCM patients with mutations in PLEKHM2 [84,85].…”

Section: Alteractions Of Interactions Between the Er And Mitochondriamentioning

confidence: 99%

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Jin

Zhang

Brundel

et al. 2019

Cells

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Cardiac disease is still the leading cause of morbidity and mortality worldwide, despite some exciting and innovative improvements in clinical management. In particular, atrial fibrillation (AF) and heart failure show a steep increase in incidence and healthcare costs due to the ageing population. Although research revealed novel insights in pathways driving cardiac disease, the exact underlying mechanisms have not been uncovered so far. Emerging evidence indicates that derailed proteostasis (i.e., the homeostasis of protein expression, function and clearance) is a central component driving cardiac disease. Within proteostasis derailment, key roles for endoplasmic reticulum (ER) and mitochondrial stress have been uncovered. Here, we describe the concept of ER and mitochondrial stress and the role of interactions between the ER and mitochondria, discuss how imbalance in the interactions fuels cardiac ageing and cardiac disease (including AF), and finally assess the potential of drugs directed at conserving the interaction as an innovative therapeutic target to improve cardiac function. of 15including the ubiquitin-proteasomal system (UPS) and autophagy [9]. In general, cellular stress, including stress caused by cardiac disease, activates multiple stress pathways, including the cytosolic heat shock response, the endoplasmic reticulum (ER) unfolded protein response (UPR ER ), and the mitochondrial UPR (UPR mt ) [10][11][12].Within the PQC, the ER and mitochondria play a critical role in the regulation of protein homeostasis and the maintenance of normal cellular function. The ER is an essential organelle involved in protein synthesis, folding, and trafficking. As protein folding is an error-prone process, the PQC system of the ER is specialized in optimizing this process, thereby preserving cardiac protein quality and homeostasis [13]. As approximately 30% of the cardiomyocyte volume is comprised of mitochondria, the maintenance of a healthy and functional mitochondrial PQC system, which includes molecular chaperones (e.g., HSP60 and HSP10) and proteases (e.g., ClpP), is critical to conserve the energy balance and cardiomyocyte function. The PQC system in mitochondria activates, upon stress, protein folding assistance mechanisms and promotes clearance of misfolded proteins to preserve mitochondrial function [14,15].Thus, a healthy proteostasis in cardiomyocytes safeguards the proper contractile function in the heart. The ER and mitochondria are essential organelles for regulating protein homeostasis, thereby guaranteeing cardiomyocyte function and survival. Therefore, a deeper understanding of ER and mitochondrial function during health and cardiac disease is required to ultimately develop novel therapeutic strategies. Role of the ER in Cardiac HealthThe ER is an essential organelle supporting multiple cellular processes such as protein synthesis, protein folding, regulation of Ca 2+ homeostasis, and contribution to the generation of autophagosomes and peroxisomes [16]. The ER lumen constitutes of a specialized fol...

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Section: Alteractions Of Interactions Between the Er And Mitochondriamentioning

confidence: 99%

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Jin

Zhang

Brundel

et al. 2019

Cells

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“…It occurs due to imbalance between myocardial blood supply and demand, resulting in development of ischaemia and induction of necrosis in myocardium. Unwarranted production of reactive oxygen species (ROS) such as superoxide radical, hydroxyl radical and nitric oxide those are extremely unstable and typically reactive is an important observation in heart failure [4][5][6]. On the whole, the treatments existing for ischaemic injury, including myocardial infarction, are directed towards reinstatement of blood supply to cardiac tissue and put off the damage imposing at the time of injury [7].…”

Section: Introductionmentioning

confidence: 99%

Apigenin Attenuates β-Receptor-Stimulated Myocardial Injury Via Safeguarding Cardiac Functions and Escalation of Antioxidant Defence System

2015

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Apigenin (AP) is a flavone in dietary flavonoids reported as strong antioxidant and elite modulator of PPARγ. The current study evaluated the consequence of AP in isoproterenol (ISO)-induced oxidative stress and myocardial infarction during β-adrenergic receptor stimulus in rats by persistent hemodynamic, biochemical and histopathological changes. Rats received AP (25, 50 and 75 mg/kg/day) or vehicle i.p. for 14 days and ISO (100 mg/kg, s.c.) on 13th and 14th days for initiation of cardiotoxicity. ISO-treated rats showed evidence of significant dwindle in systolic and diastolic arterial pressures, maximal positive rate of developed left ventricular pressure. In totting up, a noteworthy diminution in activities of creatine kinase-MB isoenzyme, reduced glutathione, superoxide dismutase, catalase and level along with rise in malondialdehyde content were observed. The shielding function of AP on isoproterenol-induced myocardial damage was observed by attenuating all the endogenous parameters and the membrane-bound enzymes. It was confirmed by histopathological examinations. The effect of AP at the doses of 50 and 75 mg/kg showed added apparent than at the dose of 25 mg/kg. Current study thus provides confirmation for protective effects of AP on myocardium in experimentally induced myocardial infarction.

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“…Assessment of AGI-026-mediated transcriptional changes in fibroblasts from a patient with D2HGA type II also revealed gene pathways with known relevance in cardiovascular system development and function (including cardiac hypertrophy), and myogenesis (personal communication, MDD and Stéphane de Botton). Cardiomyopathy has been linked to defects in myocardial energy production (Ingwall 2009), increased oxidative stress (Christiansen et al 2015), and structural defects in cardiomyocytes (Harvey and Leinwand 2011). Fatty acids are the primary source of energy in the healthy heart (Strauss and Johnson 1996), but in heart failure there is a shift toward glycolysis (Allard et al 1994).…”

Section: Discussionmentioning

confidence: 99%

A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D‐2‐hydroxyglutaric aciduria type II mouse model

Wang

Travins

Lin

et al. 2016

J of Inher Metab Disea

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D-2-hydroxyglutaric aciduria (D2HGA) type II is a rare neurometabolic disorder caused by germline gain-of-function mutations in isocitrate dehydrogenase 2 (IDH2), resulting in accumulation of D-2-hydroxyglutarate (D2HG). Patients exhibit a wide spectrum of symptoms including cardiomyopathy, epilepsy, developmental delay and limited life span. Currently, there are no effective therapeutic interventions. We generated a D2HGA type II mouse model by introducing the Idh2R140Q mutation at the native chromosomal locus. Idh2R140Q mice displayed significantly elevated 2HG levels and recapitulated multiple defects seen in patients. AGI-026, a potent, selective inhibitor of the human IDH2R140Q-mutant enzyme, suppressed 2HG production, rescued cardiomyopathy, and provided a survival benefit in Idh2R140Q mice; treatment withdrawal resulted in deterioration of cardiac function. We observed differential expression of multiple genes and metabolites that are associated with cardiomyopathy, which were largely reversed by AGI-026. These findings demonstrate the potential therapeutic benefit of an IDH2R140Q inhibitor in patients with D2HGA type II.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9960-y) contains supplementary material, which is available to authorized users.

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Impaired cardiac mitochondrial oxidative phosphorylation and enhanced mitochondrial oxidative stress in feline hypertrophic cardiomyopathy

Cited by 48 publications

References 55 publications

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Apigenin Attenuates β-Receptor-Stimulated Myocardial Injury Via Safeguarding Cardiac Functions and Escalation of Antioxidant Defence System

A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D‐2‐hydroxyglutaric aciduria type II mouse model

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