Prdm16 Deficiency Leads to Age-Dependent Cardiac Hypertrophy, Adverse Remodeling, Mitochondrial Dysfunction, and Heart Failure

Cibi, Dasan Mary; Bi-Lin, Kathleen Wung; Shekeran, Shamini Guna; Sandireddy, Reddemma; Tee, Nicole; Singh, Anamika; Wu, Yajun; Srinivasan, Dhanalakshmi; Kovalik, Jean‐Paul; Ghosh, Sujoy; Seale, Patrick; Singh, Manvendra K.

doi:10.1016/j.celrep.2020.108288

Cited by 52 publications

(71 citation statements)

References 78 publications

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“…These include i) three G protein coupled receptors, E2 (CD97), L3 (Latrophilin 3), and F5, encoded by Adgre2, Adgrl3 , and Adgrf5 , respectively; ii) the guanine nucleotide exchange factor, Dock9 , that activates Cdc42; iii) three GTPase activating proteins that are negative regulators of the GTPases Cdc42 and Rac1, namely Cdc42 GTPase-activating protein ( Cdgap or Arhgap31 ), Stard8 (Dlc2) 36 and Stard13 (Dlc3) 37 ; and iv) Cds2 (CDP-diacylglycerol synthase 2), which regulates the amount of phosphatidylinositol downstream of GPCR signaling by catalyzing the conversion of phosphatidic acid to CDP-diacylglycerol. The 13 th gene, Prdm16 , encodes a transcriptional regulator involved in brown fat metabolism, that has recently been shown to protect from cardiovascular aging 38 .…”

Section: Resultsmentioning

confidence: 99%

PTPN14, a modifier of HHT, protects SMAD4 from ubiquitination and turnover to potentiate BMP9 signaling in endothelial cells

Mamaï

Taylor

et al. 2021

Preprint

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Hereditary Hemorrhagic Telangiectasia (HHT) is a vascular condition caused by germline heterozygous loss-of-function mutations of ENG, AVCRL1, and occasionally SMAD4, encoding components of TGFβ/BMP signaling. Telangiectases occur in most HHT patients, and pulmonary, visceral, or cerebral arteriovenous malformations (AVMs) occur in 20-50%, but our understanding of how HHT mutations disrupt downstream signaling pathways causing clinical manifestations, and why some patients suffer more serious sequelae, is incomplete. We previously showed that genetic variation within PTPN14 at rs2936018 associates with the presentation of PAVM in HHT patients. Here we show rs2936018 is a cis-eQTL for PTPN14, with lower expression of the HHT at-risk allele, and that in primary human endothelial cells, PTPN14 physically interacts with the transcription factor, SMAD4, protecting it from ubiquitylation to support higher SMAD4 expression levels. In a panel of 69 lung samples, we find Ptpn14 RNA expression correlates with markers of angiogenesis, lymphangiogenesis, cell-cell interaction, BMP signaling, and rho kinase signaling, indicating preferential expression in endothelial cells. RNAScope in situ hybridization analysis and use of transgenic Ptpn14-reporter mice (Ptpn14.tm1(KOMP)Vlcg) show that Ptpn14 is predominantly but not exclusively expressed in lymphatic and vascular ECs of lung, heart and skin. In lung, Ptpn14, Acvrl1, Eng and SMAD4 expression are tightly correlated as well as with Flt1, Ece1, Sash1, and Mapk3k. Additionally, Ptpn14, Acvrl1, Eng and SMAD4 show strong expression correlation with components of G protein-coupled receptor (GPCR) signaling pathways impacting rho kinase, Cdc42, a regulator of cell migration. We report, for the first time, that in primary human endothelial cells PTPN14 binds SMAD4, as demonstrated by coimmunoprecipitation studies and confirmed by proximity ligation assay. In the nucleus, PTPN14 stabilizes SMAD4, protecting it from ubiquitylation and turnover and potentiating basal transcriptional activity from BMP and TGFβ responsive reporters, whereas in the cytoplasm PTPN14 sequesters phospho-TAZ (pTAZ) leading to TAZ turnover. PTPN14 therefore provides a physical link supporting BMP/ALK-1/SMAD4 signaling while inhibiting YAP/TAZ signaling in ECs to regulate a balance between these two pathways to maintain vascular stability. Polymorphisms in PTPN14 may alter tonic BMP/ALK-1/SMAD4 and TGFβ/TGFβRI/SMAD4 signaling to magnify ligand-mediated responses. In this way, genetic variation within PTPN14 may influence the clinical outcomes of HHT through its action on SMAD4.

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Section: Resultsmentioning

confidence: 99%

PTPN14, a modifier of HHT, protects SMAD4 from ubiquitination and turnover to potentiate BMP9 signaling in endothelial cells

Mamaï

Taylor

et al. 2021

Preprint

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“…Heart failure is one of the most fatal cardiovascular diseases worldwide. 42 It is important to identify effective therapeutic targets that inhibit maladaptive hypertrophy and subsequent heart failure. In the present study, we found that lncRNA AAB was remarkably upregulated in cardiac hypertrophy rats and this upregulation promoted ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil-like cell membrane-coated siRNA of lncRNA AABR07017145.1 therapy for cardiac hypertrophy via inhibiting ferroptosis of CMECs

Shi

Song

et al. 2022

Molecular Therapy - Nucleic Acids

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Cardiac microvascular dysfunction is associated with cardiac hypertrophy and can eventually lead to heart failure. Dysregulation of long non-coding RNAs (lncRNAs) has recently been recognized as one of the key mechanisms involved in cardiac hypertrophy. However, the potential roles and underlying mechanisms of lncRNAs in cardiac microvascular dysfunction have not been explicitly delineated. Our results confirmed that cardiac microvascular dysfunction was related to cardiac hypertrophy and ferroptosis of cardiac microvascular endothelial cells (CMECs) occurred during cardiac hypertrophy. Using a combination of in vivo and in vitro studies, we identified a lncRNA AABR07017145.1 , named as lncRNA AAB for short, and revealed that lncRNA AAB was upregulated in the hearts of cardiac hypertrophy rats as well as in the Ang II-induced CMECs. Importantly, we found that lncRNA AAB sponged and sequestered miR-30b-5p to induce the imbalance of MMP9 / TIMP1 , which enhanced the activation of transferrin receptor 1 ( TFR-1 ) and then eventually led to the ferroptosis of CMECs. Moreover, we have developed a delivery system based on neutrophil membrane (NM)-camouflaged mesoporous silica nanocomplex (MSN) for inhibition of cardiac hypertrophy, indicating the potential role of silenced lncRNA AAB (si- AAB ) and overexpressed miR-30b-5p as the novel therapy for cardiac hypertrophy.

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“…Роль PRDM16 широко изучалась в жировой ткани [15]. Одновременно с этим показана экспрессия PRDM16 в кардиомиоцитах мыши и человека [16,17].…”

Section: Discussionunclassified

“…Последующие исследования подтвердили роль вариантов, приводящих к утрате копии PRDM16, в развитии НМЛЖ и дилатационной КМП у детей [18]. В экспериментах на нокаутированных по гену PRDM16 мышах была показана роль PRDM16 в развитии гипертрофической КМП [17,19] [16], однако для однозначного вывода о связи этого гена с НМЛЖ и первичными КМП имеющихся данных недостаточно.…”

Section: Discussionunclassified

New variant of PRDM16 gene nucleotide sequence in a family with various phenotypic manifestations of the non-compacted myocardium

Myasnikov¹,

Букаева

Куликова³

et al. 2021

Russ J Cardiol

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The article presents the examination of three generations of a family with diagnosed left ventricular noncompaction (LVNC) and various phenotypic manifestations of the disease (isolated, hypertrophic and dilated type of LVNC). As a result of a molecular genetics tests, a previously undescribed single nucleotide deletion in the PRDM16 gene was revealed in all family members with the LVNC phenotype, leading to a frameshift mutation in exon 9 and the formation of a premature termination codon. This gene encodes a transcription factor responsible for after-birth suppressing the expression of genes involved in prenatal and postnatal development. Despite the presence of previous studies showing the relationship of the PRDM16 gene with LVNC development, currently there are insufficient data to prove the pathogenicity of the identified variant. However, the segregation of the symptomatic variant in three generations supports the association of the identified variant with LVNC. With the accumulation of information about changes in PRDM16 in patients with cardiomyopathies, it is possible to change the status of this gene and clarify its contribution to primary heart diseases.

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Prdm16 Deficiency Leads to Age-Dependent Cardiac Hypertrophy, Adverse Remodeling, Mitochondrial Dysfunction, and Heart Failure

Cited by 52 publications

References 78 publications

PTPN14, a modifier of HHT, protects SMAD4 from ubiquitination and turnover to potentiate BMP9 signaling in endothelial cells

PTPN14, a modifier of HHT, protects SMAD4 from ubiquitination and turnover to potentiate BMP9 signaling in endothelial cells

Neutrophil-like cell membrane-coated siRNA of lncRNA AABR07017145.1 therapy for cardiac hypertrophy via inhibiting ferroptosis of CMECs

New variant of PRDM16 gene nucleotide sequence in a family with various phenotypic manifestations of the non-compacted myocardium

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