Publication: GLP-1 RESEPTÖR AGONİSTİ LİRAGLUTİD'İN İNSAN ENDOTEL HÜCRELERİNDE YÜKSEK GLUKOZ İLE İNDÜKLENEN İNFLAMASYON İLE İLİŞKİLİ SİNYAL YOLAKLARI ÜZERİNE ETKİSİ
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Date
2023-11-25
Authors
Gökçe M.
Vidin Şen A.
Öztürk Civelek D.
Uydeş Doğan B. S.
Alp Yıldırım F. İ.
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Abstract
Amaç: Diabetes Mellitus’a bağlı olarak gelişen endotel disfonksiyonu, değişen hücre sinyalizasyonu, artan oksidatif stres ve proinflamatuvar süreçlerin aktivasyonu temelinde diyabete bağlı vasküler komplikasyonların en önemli nedenidir. İnflamasyona zemin hazırlayan immün yanıtta önemli bir rol oynayan ve patern tanıma reseptörlerinin bir üyesi olan NODbenzeri-reseptör-3 (NLRP3), inflamatuvar kaspazların aktivasyonunu, pro-interlökin-18 ve pro-interlökin-1β\"nın işlenmesini sağlayan bir protein kompleksidir. NLRP3, ASC/TMS1 ve Kaspaz-1 NLRP3 inflamazom kompleksini oluşturmaktadır. Bu çalışmada, insan endotel hücre kültürlerinde GLP-1 reseptör (GLP-1R) agonisti Liraglutid’in inflamasyona zemin hazırlayan immün yanıt yolakları ile ilişkili hedef moleküller üzerine etkisinin araştırılması amaçlanmıştır. Gereç-Yöntem: HUVEC (İnsan umbilikal ven endotel hücreleri) ve HCAEC (İnsan koroner arter endotel hücreleri), normoglisemik (5.5mM) veya hiperglisemik ortamda (25 mM) 48 saat boyunca Liraglutid’in 10 nM ve 100 nM lik konsantrasyonları ile inkübe edilmiştir. Ardından LDH (laktat dehidrogeneaz) testi ile canlılık tayini yapılmıştır. RT-PCR testi ile NLRP3 inflamazom kompleksinin üyeleri olan ASC/TMS1 ve Kaspaz-1 mRNA ekspresyonları ölçülmüştür. Bulgular: HUVEC’de LDH seviyelerinde anlamlı bir değişikliğe neden olmamasına karşın Liraglutid 100 nM’de LDH seviyelerini azaltmıştır. Hiperglisemik ortam HUVEC’de Kaspaz-1 mRNA düzeylerinde artışa neden olmuşken HCAEC’de bir değişim olmamıştır. Liraglutid 10 nM’de, HCAEC’de hiperglisemi ile artan Kaspaz-1 mRNA düzeylerini baskılarken, HUVEC’de etkisiz bulunmuştur. ASC/TMS1 mRNA düzeyleri HUVEC’de hiperglisemik ortamda artarken, HCAEC’de anlamlı bir değişime neden olmamıştır. HCAEC’de ASC/TMS1 mRNA düzeylerinde gözlenen söz konusu artış Liraglutid varlığında azalırken (10 nM’de) HUVEC’de Liraglutid inkübasyonu ile bir değişiklik olmamıştır. Sonuç: Bu çalışmanın sonuçları, Liraglutid\"in insan kaynaklı venöz ve arteriyel endotel hücrelerinde hiperglisemi ile indüklenen inflamasyon ve immün yanıt aktivasyonuna bağlı olarak oluşan hücresel hasarı azaltma potansiyelinin olabileceğine işaret etmektedir. Anahtar Kelimeler: Endotel, İnflamasyon, Liraglutid, NLRP3, Hiperglisemi
Aim: Endothelial dysfunction induced by Diabetes Mellitus, altered cell signaling, increased oxidative stress, and activation of proinflammatory processes which are the most significant reasons for vascular complications associated with diabetes. NODlike receptor-3 (NLRP3), a member of pattern recognition receptors that play an important role in the immune response predisposing to inflammation, is a protein complex that enables the activation of inflammatory caspases and processing of pro-interleukin-18 and pro-interleukin-1β. NLRP3 forms the NLRP3 inflammasome complex with ASC/TMS1 and Caspase-1. This study aimed to investigate the effects of the GLP-1 receptor (GLP-1R) agonist Liraglutide on target molecules associated with immune response pathways that predispose inflammation in human endothelial cell cultures. Materials and Methods: Human umbilical vein endothelial cells (HUVEC) and human coronary artery endothelial cells (HCAEC) were incubated with Liraglutide at concentrations of 10 nM and 100 nM, in normoglycemic (5.5 mM) or hyperglycemic (25 mM) conditions for 48 hours. Cell viability was determined by LDH (lactate dehydrogenase) assay. The mRNA expressions of ASC/TMS1 and Caspase-1, members of the NLRP3 inflammasome complex, were measured by using RTPCR. Results: In HUVEC, although there was no significant change in LDH levels, Liraglutide at 100 nM reduced LDH levels. Hyperglycemic conditions led to an increase in Caspase-1 mRNA levels in HUVEC, while no change was observed in HCAEC. Liraglutide at 10 nM suppressed the increased Caspase-1 mRNA levels due to hyperglycemia in HCAEC, but had no effect in HUVEC. ASC/TMS1 mRNA levels increased in hyperglycemic conditions in HUVEC, while no significant change was observed in HCAEC. The increase in ASC/TMS1 mRNA levels in HCAEC was reduced in the presence of Liraglutide (at 10 nM), while there was no change in HUVEC with Liraglutide incubation. Conclusion: This study suggests that, Liraglutide may have the potential to reduce cellular damage caused by inflammation and immune response activation due to hyperglycemia in human venous and arterial endothelial cells. Keywords: Endothelium, Inflammation, Liraglutide, NLRP3, Hyperglycemia
Aim: Endothelial dysfunction induced by Diabetes Mellitus, altered cell signaling, increased oxidative stress, and activation of proinflammatory processes which are the most significant reasons for vascular complications associated with diabetes. NODlike receptor-3 (NLRP3), a member of pattern recognition receptors that play an important role in the immune response predisposing to inflammation, is a protein complex that enables the activation of inflammatory caspases and processing of pro-interleukin-18 and pro-interleukin-1β. NLRP3 forms the NLRP3 inflammasome complex with ASC/TMS1 and Caspase-1. This study aimed to investigate the effects of the GLP-1 receptor (GLP-1R) agonist Liraglutide on target molecules associated with immune response pathways that predispose inflammation in human endothelial cell cultures. Materials and Methods: Human umbilical vein endothelial cells (HUVEC) and human coronary artery endothelial cells (HCAEC) were incubated with Liraglutide at concentrations of 10 nM and 100 nM, in normoglycemic (5.5 mM) or hyperglycemic (25 mM) conditions for 48 hours. Cell viability was determined by LDH (lactate dehydrogenase) assay. The mRNA expressions of ASC/TMS1 and Caspase-1, members of the NLRP3 inflammasome complex, were measured by using RTPCR. Results: In HUVEC, although there was no significant change in LDH levels, Liraglutide at 100 nM reduced LDH levels. Hyperglycemic conditions led to an increase in Caspase-1 mRNA levels in HUVEC, while no change was observed in HCAEC. Liraglutide at 10 nM suppressed the increased Caspase-1 mRNA levels due to hyperglycemia in HCAEC, but had no effect in HUVEC. ASC/TMS1 mRNA levels increased in hyperglycemic conditions in HUVEC, while no significant change was observed in HCAEC. The increase in ASC/TMS1 mRNA levels in HCAEC was reduced in the presence of Liraglutide (at 10 nM), while there was no change in HUVEC with Liraglutide incubation. Conclusion: This study suggests that, Liraglutide may have the potential to reduce cellular damage caused by inflammation and immune response activation due to hyperglycemia in human venous and arterial endothelial cells. Keywords: Endothelium, Inflammation, Liraglutide, NLRP3, Hyperglycemia
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Keywords
Eczacılık, Meslek Bilimleri, Farmakoloji, Sağlık Bilimleri, Pharmacology and Therapeutics, Professional Sciences, Pharmacology, Health Sciences, Klinik Tıp (MED), Yaşam Bilimleri (LIFE), Farmakoloji ve Toksikoloji, FARMAKOLOJİ VE ECZACILIK, Clinical Medicine (MED), Life Sciences (LIFE), PHARMACOLOGY & TOXICOLOGY, PHARMACOLOGY & PHARMACY, Farmakoloji, Toksikoloji ve Eczacılık (çeşitli), Genel Farmakoloji, Toksikoloji ve Eczacılık, Farmakoloji (tıbbi), İlaç Rehberleri, Yaşam Bilimleri, Pharmacy, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), General Pharmacology, Toxicology and Pharmaceutics, Pharmacology (medical), Drug Guides, Life Sciences
Citation
Gökçe M., Vidin Şen A., Öztürk Civelek D., Uydeş Doğan B. S., Alp Yıldırım F. İ., \"GLP-1 RESEPTÖR AGONİSTİ LİRAGLUTİD'İN İNSAN ENDOTEL HÜCRELERİNDE YÜKSEK GLUKOZ İLE İNDÜKLENEN İNFLAMASYON İLE İLİŞKİLİ SİNYAL YOLAKLARI ÜZERİNE ETKİSİ\", 2. Uluslararası ve 27. Ulusal Farmakoloji Kongresi , Antalya, Türkiye, 23 - 26 Kasım 2023, ss.215-216