Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation

Lee, Sun Joo; Jeong, Ji Yun; Oh, Chang Joo; Park, Sungmi; Kim, Joon‐Young; Kim, Han Jong; Kim, Nam Doo; Choi, Young Keun; Yeon, Ji; Go, Younghoon; Ha, Chae Myung; Choi, Je Yong; Huh, Seung; Jeoung, Nam Ho; Lee, Ki Up; Choi, Hueng Sik; Wang, Yudong; Park, Keun Gyu; Harris, Robert A.; Lee, In Kyu

doi:10.1038/srep16577

Cited by 57 publications

(77 citation statements)

References 54 publications

(67 reference statements)

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“…[41][42][43][44][45][46] PDK4 can also directly phosphorylate SMADs 1/5/8 and regulate their activity. 47 Because deregulated or reduced BMP signaling is a common feature of PAH, 8,48 it is not surprising that the gene expression trends would be similar in the skin MCs from BMPR2-mutant, CAV1-mutant, and IPAH patients.…”

Section: Discussionmentioning

confidence: 99%

Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

et al. 2016

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Rapid access to lung-derived cells from stable subjects is a major challenge in the pulmonary hypertension field, given the relative contraindication of lung biopsy. In these studies, we sought to demonstrate the importance of evaluating a cell type that actively participates in disease processes, as well as the potential to translate these findings to vascular beds in other nonlung tissues, in this instance perivascular skin mesenchymal cells (MCs). We utilized posttransplant or autopsy lung explant-derived cells (ABCG2-expressing mesenchymal progenitor cells [MPCs], fibroblasts) and skin-derived MCs to test the hypothesis that perivascular ABCG2 MPCs derived from pulmonary arterial hypertension (PAH) patient lung and skin would express a gene profile reflective of ongoing vascular dysfunction. By analyzing the genetic signatures and pathways associated with abnormal ABCG2 lung MPC phenotypes during PAH and evaluating them in lung-and skinderived MCs, we have identified potential predictor genes for detection of PAH as well as a targetable mechanism to restore MPCs and microvascular function. These studies are the first to explore the utility of expanding the study of ABCG2 MPC regulation of the pulmonary microvasculature to the epidermis, in order to identify potential markers for adult lung vascular disease, such as PAH.Keywords: mesenchymal progenitor cells, skin, lung, microvascular, pulmonary hypertension, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, BMPR2, Wnt signaling, LRP6, DKK1. Pulmonary vascular dysfunction or disease (PVD) is characterized by altered lung vascular structure and function. A significant loss of vascular-bed function, as seen in PVD, is thought to precede the clinical presentation of pulmonary hypertension (PH). 1 PH is associated with a wide array of comorbid conditions, such as systemic sclerosis, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis, and also occurs as a primary PVD known as either idiopathic pulmonary arterial hypertension (IPAH) or heritable pulmonary arterial hypertension (HPAH). 2-4 PH is characterized by elevated pulmonary artery pressures and widespread vascular remodeling, including endothelial cell dysfunction and occlusion or rarefaction of the peripheral pulmonary microvasculature. 5-7 All forms of PH have a high mortality rate despite current therapeutic options. The current limited understanding of PVD as a predecessor to PH and lack of diagnostic approaches or criteria specific to preclinical PVD have hampered the study of the early stages of PVD in both rodent models and the clinical setting.Approximately 80% of HPAH patients have a known mutation in the gene bone morphogenetic protein receptor type 2 (BMPR2). BMPR2 mutation-associated PAH is an autosomal dominant disease with low penetrance (approx. 20%); hence, not all mutation carriers develop PAH. In addition, approximately 20% of patients initially labeled as having IPAH also have a mutation in BMPR2 and thus heritable disease. 8 In addition to ge...

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Section: Discussionmentioning

confidence: 99%

Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

et al. 2016

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“…PDK, which consists of four isotypes, is a main regulator of the pyruvate dehydrogenase complex (PDC), a master regulator of cellular energy metabolism in mitochondria [195]. Among the four isotypes, the role of PDK4, in VC, by induction of osteogenic differentiation of VSMCs, was reported [196,197], while phosphorylation of PDHE1α was localized to calcified lesions in VC patients. In addition, high inorganic phosphate (Pi)-induces PDK4 expression, and elicits phosphorylation of PDHE1α, in VSMCs, but not in PDKs 1, 2, or 3.…”

Section: Pyruvate Dehydrogenase Kinase (Pdk)4mentioning

confidence: 99%

Vascular Calcification—New Insights into Its Mechanism

Lee

Jeon

2020

IJMS

Self Cite

258

254

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Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few decades have seen extensive research into VC, revealing that the mechanism of VC is not merely a consequence of a high-phosphorous and -calcium milieu, but also occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anticalcific events. In addition to traditionally established osteogenic signaling, dysfunctional calcium homeostasis is prerequisite in the development of VC. Moreover, loss of defensive mechanisms, by microorganelle dysfunction, including hyper-fragmented mitochondria, mitochondrial oxidative stress, defective autophagy or mitophagy, and endoplasmic reticulum (ER) stress, may all contribute to VC. To facilitate the understanding of vascular calcification, across any number of bioscientific disciplines, we provide this review of a detailed updated molecular mechanism of VC. This encompasses a vascular smooth muscle phenotypic of osteogenic differentiation, and multiple signaling pathways of VC induction, including the roles of inflammation and cellular microorganelle genesis.

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“…Additionally, mitochondrial dysfunction has been shown to be important in many of the clinical features seen in CS individuals, such as basal ganglia calcification (Finsterer and Kopsa, 2005), sensorineural hearing loss (Han and Someya, 2013; Someya and Prolla, 2010),optic atrophy (Lascaratos et al, 2015), retinal degeneration (Mao et al, 2014), and vascular calcification and atherosclerosis (Kim et al, 2012; Lee et al, 2015; Villa-Bellosta et al, 2013; Yu et al, 2013). Mitochondrial dysfunction also has important roles in neurodegeneration (Calì et al, 2012; Cheng et al, 2016b; Krols et al, 2016), that could be mediated through other neurotrophic factors such as brain-derived neurotrophic factor (Su et al, 2014).…”

Section: 4 Cs Resembles Mitochondrial Diseasesmentioning

confidence: 99%

Cockayne syndrome: Clinical features, model systems and pathways

Karikkineth

Scheibye‐Knudsen

Fivenson

et al. 2017

Ageing Research Reviews

200

174

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Cockayne syndrome (CS) is a disorder characterized by a variety of clinical features including cachectic dwarfism, severe neurological manifestations including microcephaly and cognitive deficits, pigmentary retinopathy, cataracts, sensorineural deafness, and ambulatory and feeding difficulties, leading to death by 12 years of age on average. It is an autosomal recessive disorder, with a prevalence of approximately 2.5 per million. There are several phenotypes (1, 2 and 3) and complementation groups (CSA and CSB), and overlaps with xeroderma pigmentosum (XP). It has been considered a progeria, and many of the clinical features resemble accelerated aging. As such, the study of CS affords an opportunity to better understand the underlying mechanisms of aging. The molecular basis of CS has traditionally been considered to be due to defects in transcription and transcription-coupled nucleotide excision repair (TC-NER). However, recent work suggests that defects in base excision DNA repair and mitochondrial functions may also play key roles. This opens up the possibility of molecular interventions in CS, and by extrapolation, possibly in aging.

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Pyruvate Dehydrogenase Kinase 4 Promotes Vascular Calcification via SMAD1/5/8 Phosphorylation

Cited by 57 publications

References 54 publications

Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

Vascular Calcification—New Insights into Its Mechanism

Cockayne syndrome: Clinical features, model systems and pathways

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