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Coronary Artery Dis...
Coronary Artery Disease Risk Variant Dampens the Expression of CALCRL by Reducing HSF Binding to Shear Stress Responsive Enhancer in Endothelial Cells In Vitro
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- Selvarajan, Ilakya (författare)
- Univ Eastern Finland, AI Virtanen Inst Mol Sci, Neulaniementie 2, Kuopio 70210, Finland.
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- Kiema, Miika (författare)
- Univ Eastern Finland, AI Virtanen Inst Mol Sci, Neulaniementie 2, Kuopio 70210, Finland.
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- Huang, Ru-Ting (författare)
- Univ Chicago, Dept Med, Chicago, IL USA.
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- Li, Jin (författare)
- Univ Chicago, Dept Med, Chicago, IL USA.
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- Zhu, Jiayu (författare)
- Univ Chicago, Dept Med, Chicago, IL USA.
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- Polonen, Petri (författare)
- Univ Eastern Finland, Inst Biomed, Sch Med, Kuopio, Finland.
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- Ord, Tiit (författare)
- Univ Eastern Finland, AI Virtanen Inst Mol Sci, Neulaniementie 2, Kuopio 70210, Finland.
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- Ounap, Kadri (författare)
- Univ Eastern Finland, AI Virtanen Inst Mol Sci, Neulaniementie 2, Kuopio 70210, Finland.
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- Godiwala, Mehvash (författare)
- Univ Eastern Finland, AI Virtanen Inst Mol Sci, Neulaniementie 2, Kuopio 70210, Finland.
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- Golebiewski, Anna Kathryn (författare)
- Univ Arizona, Coll Med, Dept Cellular & Mol Med, Tucson, AZ USA.
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- Ravindran, Aarthi (författare)
- Univ Eastern Finland, AI Virtanen Inst Mol Sci, Neulaniementie 2, Kuopio 70210, Finland.
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- Maeklin, Kiira (författare)
- Univ Eastern Finland, AI Virtanen Inst Mol Sci, Neulaniementie 2, Kuopio 70210, Finland.
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- Toropainen, Anu (författare)
- Univ Eastern Finland, AI Virtanen Inst Mol Sci, Neulaniementie 2, Kuopio 70210, Finland.
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- Stolze, Lindsey K. (författare)
- Univ Arizona, Coll Med, Dept Cellular & Mol Med, Tucson, AZ USA.
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- Arce, Maximiliano (författare)
- Uppsala universitet,Vaskulärbiologi
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- Magnusson, Peetra (författare)
- Uppsala universitet,Vaskulärbiologi
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- White, Stephen (författare)
- Newcastle Univ, Biosci Inst, Fac Med Sci, Newcastle Upon Tyne, England.
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- Romanoski, Casey E. (författare)
- Univ Arizona, Coll Med, Dept Cellular & Mol Med, Tucson, AZ USA.
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- Heinaniemi, Merja (författare)
- Univ Eastern Finland, Inst Biomed, Sch Med, Kuopio, Finland.
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- Laakkonen, Johanna P. (författare)
- Univ Eastern Finland, AI Virtanen Inst Mol Sci, Neulaniementie 2, Kuopio 70210, Finland.
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- Fang, Yun (författare)
- Univ Chicago, Dept Med, Chicago, IL USA.
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- Kaikkonen, Minna U. (författare)
- Univ Eastern Finland, AI Virtanen Inst Mol Sci, Neulaniementie 2, Kuopio 70210, Finland.
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Univ Eastern Finland, AI Virtanen Inst Mol Sci, Neulaniementie 2, Kuopio 70210, Finland Univ Chicago, Dept Med, Chicago, IL USA. (creator_code:org_t)
- Lippincott Williams & Wilkins, 2024
- 2024
- Engelska.
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : Lippincott Williams & Wilkins. - 1079-5642 .- 1524-4636. ; 44:6, s. 1330-1345
- Relaterad länk:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- BACKGROUND:CALCRL (calcitonin receptor-like) protein is an important mediator of the endothelial fluid shear stress response, which is associated with the genetic risk of coronary artery disease. In this study, we functionally characterized the noncoding regulatory elements carrying coronary artery disease that risks single-nucleotide polymorphisms and studied their role in the regulation of CALCRL expression in endothelial cells.METHODS:To functionally characterize the coronary artery disease single-nucleotide polymorphisms harbored around the gene CALCRL, we applied an integrative approach encompassing statistical, transcriptional (RNA-seq), and epigenetic (ATAC-seq [transposase-accessible chromatin with sequencing], chromatin immunoprecipitation assay-quantitative polymerase chain reaction, and electromobility shift assay) analyses, alongside luciferase reporter assays, and targeted gene and enhancer perturbations (siRNA and clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) in human aortic endothelial cells.RESULTS:We demonstrate that the regulatory element harboring rs880890 exhibits high enhancer activity and shows significant allelic bias. The A allele was favored over the G allele, particularly under shear stress conditions, mediated through alterations in the HSF1 (heat shock factor 1) motif and binding. CRISPR deletion of rs880890 enhancer resulted in downregulation of CALCRL expression, whereas HSF1 knockdown resulted in a significant decrease in rs880890-enhancer activity and CALCRL expression. A significant decrease in HSF1 binding to the enhancer region in endothelial cells was observed under disturbed flow compared with unidirectional flow. CALCRL knockdown and variant perturbation experiments indicated the role of CALCRL in mediating eNOS (endothelial nitric oxide synthase), APLN (apelin), angiopoietin, prostaglandins, and EDN1 (endothelin-1) signaling pathways leading to a decrease in cell proliferation, tube formation, and NO production.CONCLUSIONS:Overall, our results demonstrate the existence of an endothelial-specific HSF (heat shock factor)-regulated transcriptional enhancer that mediates CALCRL expression. A better understanding of CALCRL gene regulation and the role of single-nucleotide polymorphisms in the modulation of CALCRL expression could provide important steps toward understanding the genetic regulation of shear stress signaling responses.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Kardiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)
Nyckelord
- coronary artery disease
- coronary vessels
- gene expression
- genome-wide association study
- polymorphism
- single nucleotide
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Till lärosätets databas
- Av författaren/redakt...
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Selvarajan, Ilak ...
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Kiema, Miika
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Huang, Ru-Ting
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Li, Jin
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Zhu, Jiayu
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Polonen, Petri
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visa fler...
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Ord, Tiit
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Ounap, Kadri
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Godiwala, Mehvas ...
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Golebiewski, Ann ...
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Ravindran, Aarth ...
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Maeklin, Kiira
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Toropainen, Anu
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Stolze, Lindsey ...
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Arce, Maximilian ...
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Magnusson, Peetr ...
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White, Stephen
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Romanoski, Casey ...
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Heinaniemi, Merj ...
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Laakkonen, Johan ...
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Fang, Yun
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Kaikkonen, Minna ...
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Arteriosclerosis ...
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