Investigation of Differentially Expressed Genes in the Ventricular Myocardium of Senescent Rats

Ishihata, Akira

doi:10.1196/annals.1354.017

Cited by 8 publications

(4 citation statements)

References 9 publications

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“…The specific regulatory control of ATP5MC genes remains unstudied, but expression assays suggest that the expression levels of ATP5MC1, 2, and 3 respond independently when exposed to the same stressor. [34][35][36][37][38][39][40] Differential expression patterns for ATP5MC genes within the nervous system (eg, striatum vs. spinal cord) or resulting from environmental factors such as oxidative stress [39][40][41][42] might increase the proportion of mutant ATP5MC3, influencing the phenotype.…”

Section: Discussionmentioning

confidence: 99%

A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia

et al. 2021

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Background In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24‐2q31. Objective The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia. Methods Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the “GeneMatcher” program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient‐derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function. Results Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper‐limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility. Conclusion A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.

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Section: Discussionmentioning

confidence: 99%

A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia

et al. 2021

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“…Aging is associated with higher endogenous ET-1 levels (mRNA and protein) in both plasma and vascular tissue in males and females (10,36,53,57) together with an altered ET A to ET B ratio (48). Functionally, an increase in ET-1-dependent vascular tone has been demonstrated in clinically healthy older men (99).…”

Section: Endothelin System In Agingmentioning

confidence: 97%

Endothelin in the female vasculature: a role in aging?

Lekontseva

Chakrabarti

Davidge

2010

American Journal of Physiology-Regulatory, Integrative and Comp

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vascular diseases are the leading cause of morbidity and mortality in the world. Aging is associated with an increased incidence of cardiovascular disease. Premenopausal women are relatively protected from vascular alterations compared with age-matched men, likely due to higher levels of the female sex hormones. However, these vasoprotective effects in women are attenuated after menopause. Thus, the vascular system in aging women is affected by both the aging process as well as loss of hormonal protection, positioning women of this age group at a high risk for cardiovascular diseases such as hypertension, myocardial infarction, and stroke. The endothelin system in general and endothelin-1 (ET-1) in particular plays an important role in the pathogenesis of vascular dysfunction associated with aging. Evidence suggests that the female sex steroids can interfere with the vascular expression and actions of ET-1 via several mechanisms, which may further contribute to pathological processes in the vasculature of aging women. In this review, we have summarized hormone-dependent vascular pathways whereby ET-1 may mediate the deleterious effects of aging in postmenopausal females.ET-1; menopause; estrogen; vasoconstriction; inflammation AGING OF THE VASCULAR SYSTEM is a complex process characterized by sustained proinflammatory and proconstrictor changes in the vascular microenvironment. The resulting structural and functional alterations in systemic vasculature lead to increased risk of cardiovascular diseases such as hypertension, myocardial infarction, and stroke in the aging population (12,18,51,70). In the absence of chronic preexisting conditions, such as diabetes, premenopausal women express a favorable cardiovascular phenotype compared with age-matched men, largely due to the vasoprotective role of ovarian steroids such as estrogen (92). An alteration in circulating sex hormones at menopause, such as the decrease in estrogens and a relative excess of androgens, is associated with the conversion from a low-to high-risk cardiovascular profile (19,56). Although the mechanisms underlying the pathogenesis of vascular dysfunction in postmenopausal women are not completely understood, it is believed to result from a complex interplay between the aging process and the decline in ovarian hormones like estrogen.Endothelin has emerged as one of the key mediators of vascular dysfunction and remodeling in aging. Interestingly, there is evidence that female sex steroids (in particular, estrogen) can regulate the endothelin system at various levels from gene transcription and posttranslational modification of the peptide to expression of its vascular receptors and postreceptor signaling events. This review will summarize current knowledge on the impact of aging and female sex hormones on the endothelin system, as well as outline directions where further research is needed. A better understanding of the role of endothelin in the pathogenesis of vascular dysfunction in postmenopausal women may lead to the development of novel sex-...

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“…In old mice, ET-1 receptor A signalling suppresssed EDD [ 28 ]. Indeed, elevated endogenous ET-1 mRNA and protein levels in plasma and vascular tissue have been associated with ageing in both female and male rats [ 180 , 181 ]. In studies with aged mice and rats, they observed ET-1 dampened vasoconstriction (albeit increased ET-1 concentrations) potentially due to functional inability of endothelin receptor signalling pathways [ 179 , 182 , 183 ].…”

Section: Et-1 Age and Ageing: Is Differential Diagnostic Approach Feasible?mentioning

confidence: 99%

Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine

et al. 2021

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Endothelin-1 (ET-1) is involved in the regulation of a myriad of processes highly relevant for physical and mental well-being; female and male health; in the modulation of senses, pain, stress reactions and drug sensitivity as well as healing processes, amongst others. Shifted ET-1 homeostasis may influence and predict the development and progression of suboptimal health conditions, metabolic impairments with cascading complications, ageing and related pathologies, cardiovascular diseases, neurodegenerative pathologies, aggressive malignancies, modulating, therefore, individual outcomes of both non-communicable and infectious diseases such as COVID-19. This article provides an in-depth analysis of the involvement of ET-1 and related regulatory pathways in physiological and pathophysiological processes and estimates its capacity as a predictor of ageing and related pathologies, a sensor of lifestyle quality and progression of suboptimal health conditions to diseases for their targeted prevention and as a potent target for cost-effective treatments tailored to the person.

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Investigation of Differentially Expressed Genes in the Ventricular Myocardium of Senescent Rats

Cited by 8 publications

References 9 publications

A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia

A Novel Variant of ATP5MC3 Associated with Both Dystonia and Spastic Paraplegia

Endothelin in the female vasculature: a role in aging?

Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine

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