Cardiac Fas-Dependent and Mitochondria-Dependent Apoptotic Pathways in a Transgenic Mouse Model of Huntington’s Disease

Wu, Bor Tsang; Chiang, Ming‐Chang; Tasi, Ching Yi; Kuo, Chia‐Hua; Shyu, Woei Cherng; Kao, Chung Lan; Huang, Chih Yang; Lee, Shin-Da

doi:10.1007/s12012-015-9318-y

Cited by 13 publications

(25 citation statements)

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“…These morphological changes may lead directly to cardiac energy metabolism imbalances. Indeed, a recent study suggested that cardiac Fas-dependent and mitochondria-dependent apoptotic pathways were activated in R6/2 hearts [38]. Mitochondrial structure disarrangement may thus result in an energy status imbalance in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of resynthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings.Keywords: Huntington's disease, cardiomyopathy, arrhythmia, energy imbalance, catabolism of nucleotides, heart failure 3 SUMMARY Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related cardiomyopathy has been widely described in different mouse models, however there is little known about the source of the pathological remodelling in HD hearts. We found that contractile dysfunction in HD settings might be caused by components of cellular energy imbalance, changes in catabolism of adenine nucleotides, steady-state internal redox derangements and an activation of AMPK, leading to a shift in the cardiac substrate preference. These changes were accompanied by increased concentrations of adenine nucleotide catabolites (inosine, hypoxanthine, xanthine and uric acid) and uridine in both HD mouse models and HD patients' plasma. These metabolites represent the first identified biomarkers related to striated muscle dysfunction in HD. Our study explores a mechanism that might lead to HD-related cardiomyopathy and opens new avenues for therapeutic treatments in HD. HIGHLIGHTS• Heart dysfunction in HD is caused by the altered metabolism of nucleotides in vivo • Altered energy imbalances may lead to heart malfunction in HD in vivo• Increased lev...

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Section: Discussionmentioning

confidence: 99%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Additional alterations in HD patients include subcellular abnormalities in fibroblasts, circadian dysfunction [27–31], lymphocytes [32, 33], and erythrocytes [9]. Growing evidence now suggests that cells from cardiac and muscle tissues of HD patients bear aberrations related to the expression of mutant HTT [11, 14–19, 34–43]. Besides the cardiac abnormalities (described below), skeletal muscle dysfunction is very common in HD patients and leads to severe muscle wasting [11, 19].…”

Section: Peripheral Pathology Associated With Huntington’s Diseasementioning

confidence: 99%

“…Other studies have shown that expression of mutant HTT leads to intracellular aggregate formation in peripheral tissues and gene expression changes in HD peripheral tissues sections [10, 47]. Other abnormalities such as endocrine dysfunction, blood tissue abnormalities, and cell death in peripheral tissues have also been reported in both HD patients and animal models [11, 14–19, 34–43]. …”

Section: Peripheral Pathology Associated With Huntington’s Diseasementioning

confidence: 99%

“…Epidemiological studies have suggested a link between HD and cardiac dysfunction, including cardiac amyloidosis, a group of disorders characterized by protein misfolding and the accumulation of aggregates in the heart [13, 48, 50]. It is well known that HTT is also expressed in the heart; however, until recently, it was unclear whether cardiac pathology in HD patients is primarily due to expression of mutant HTT in the cardiomyocytes, to the brain dysfunction, or to the CNS malfunctions [34, 35, 37, 39, 43]. …”

Section: Huntington’s Disease-induced Cardiac Abnormalitiesmentioning

confidence: 99%

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Huntington’s Disease-Induced Cardiac Disorders Affect Multiple Cellular Pathways

Melkani

2016

ROS

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Huntington’s disease (HD) is a rare, inherited, progressive, and fatal neurological disorder resulting from expanded polyglutamine repeats in the huntingtin protein. While HD is predominately characterized as a disease of the central nervous system, mortality surveys and epidemiological studies reveal heart disease as one of the leading causes of death in HD patients. Emerging evidence supports a link between HD and cardiovascular disease, such as cardiac amyloidosis (accumulation of aggregates in the heart). Experimental animal and clinical studies have attempted to explain the mechanisms of HD-induced cardiac pathology in the association of protein misfolding, autophagic defects, oxidative stress, mitochondrial dysfunction, and cell death. HD is increasingly understood as a complex disease with peripheral components of cardiac and skeletal muscle pathophysiology. While the discovery of these linkages and apparent pathological markers is promising, the mechanism of HD-induced cardiac pathology and the nature of its cell autonomy remain elusive. Further study of the wide-ranging cardiac function in HD patients is needed. This review highlights published literature on the pathological factors associated with HD-induced cardiac amyloidosis and other cardiovascular diseases, and addresses gaps in this expanding area of study. Through comprehensive experimental and clinical studies, potential drugs can be tested to attenuate and/or ameliorate HD-induced cardiac pathology and mortality.

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“…The AKT family is an upstream factor of Bax and negatively regulates Bax expression. The function of Bax during ischemia has been well documented, and plays a crucial role in mitochondrial-dependent apoptosis (Bax, cytosolic Cyto C, activated caspase-9 and activated caspase-3) via inducing mitochondrial permeabilization and therefore the release of apoptogenic factors [25,36,37]. As shown in our data, significant increases of Bax protein abundance and disrupted MOMP are in accordance with elevated apoptotic rates observed in cardiomyocytes with AKT2 inhibition during ischemia, suggesting severe disruption of MOMP with additional AKT2 blockage.…”

Section: Discussionmentioning

confidence: 99%

AKT2 Blocks Nucleus Translocation of Apoptosis-Inducing Factor (AIF) and Endonuclease G (EndoG) While Promoting Caspase Activation during Cardiac Ischemia

Zhao

et al. 2017

IJMS

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The AKT (protein kinase B, PKB) family has been shown to participate in diverse cellular processes, including apoptosis. Previous studies demonstrated that protein kinase B2 (AKT2−/−) mice heart was sensitized to apoptosis in response to ischemic injury. However, little is known about the mechanism and apoptotic signaling pathway. Here, we show that AKT2 inhibition does not affect the development of cardiomyocytes but increases cell death during cardiomyocyte ischemia. Caspase-dependent apoptosis of both the extrinsic and intrinsic pathway was inactivated in cardiomyocytes with AKT2 inhibition during ischemia, while significant mitochondrial disruption was observed as well as intracytosolic translocation of cytochrome C (Cyto C) together with apoptosis-inducing factor (AIF) and endonuclease G (EndoG), both of which are proven to conduct DNA degradation in a range of cell death stimuli. Therefore, mitochondria-dependent cell death was investigated and the results suggested that AIF and EndoG nucleus translocation causes cardiomyocyte DNA degradation during ischemia when AKT2 is blocked. These data are the first to show a previous unrecognized function and mechanism of AKT2 in regulating cardiomyocyte survival during ischemia by inducing a unique mitochondrial-dependent DNA degradation pathway when it is inhibited.

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Cardiac Fas-Dependent and Mitochondria-Dependent Apoptotic Pathways in a Transgenic Mouse Model of Huntington’s Disease

Cited by 13 publications

References 36 publications

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Huntington’s Disease-Induced Cardiac Disorders Affect Multiple Cellular Pathways

AKT2 Blocks Nucleus Translocation of Apoptosis-Inducing Factor (AIF) and Endonuclease G (EndoG) While Promoting Caspase Activation during Cardiac Ischemia

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