ANJİYOTENSİN II’NİN YÜKSEK GLUKOZLU ORTAMDA VASKÜLER DÜZ KAS HÜCRE PROLİFERASYONUNA ETKİSİ

Year 2022, , 399 - 405, 17.10.2022

Mustafa Kırça

https://doi.org/10.18229/kocatepetip.929287

Abstract

AMAÇ: Anjiyotensin II (Ang II)’nin damar duvarındaki asıl hedefi vasküler düz kas hücreleri (VDKH)’dir. Bu hücrelerin proliferasyonunu uyararak ateroskleroz ve hipertansiyon patogenezine katılır. Yüksek konsantrasyondaki glukoz (YG) da bu hücrelerde proliferasyonu artırarak diyabetlilerde görülen hızlandırılmış ateroskleroz sürecine katkıda bulunur. Bununla birlikte karşıt görüşte çalışmalar da mevcuttur. Bu çalışmada Ang II ve YG’un VDKH proliferasyonuna etkisinin belirlenmesi amaçlandı. Bu amaçla düşük glukoz (DG, 5,5 mM) ve yüksek glukoz (YG, 25 mM) ortamında Ang II’nin 24, 48 ve 72 saat sonunda VDKH proliferasyonuna etkisi incelendi. Ayrıca Ang II uyarımlı proliferasyonda AT1R inhibitörleri telmisartan ve irbesartana ek olarak p38 ve ERK1/2 MAPK ve NF-κB rolleri araştırıldı. Son olarak proliferasyon verisini desteklemek için Ang II uyarımlı ERK1/2 MAPK fosforilasyonu ölçüldü.
GEREÇ VE YÖNTEM: Çalışmada sıçan aortundan izole edilen primer VDKH kullanıldı. Proliferasyon, Wst-1 tuzu kullanılarak spektrofotometrik olarak ölçüldü. ERK1/2 MAPK fosforilasyonu western blot yöntemiyle belirlendi.
BULGULAR: Ang II ve YG tek başına uygulandığında en yüksek proliferasyon 24 saat sonunda gözlendi. DG ortamında Ang II’nin proliferasyonu yaklaşık 1.7 kat, YG’un ise 1.5 kat artırdığı belirlendi. Ang II’nin YG ile 48 saat uygulanması hücre proliferasyonunu %25 daha fazla artırdı. Telmisartan ve irbesartan Ang II uyarımlı artmış proliferasyonu baskıladı. NF-κB inhibisyonunun önemli oranda artmış VDKH proliferasyonu ile sonuçlandığı tespit edildi. P38 ve ERK1/2 MAPK inhibisyonu ile proliferasyonun azaldığı gözlendi. Son olarak proliferasyon ölçümlerine paralel şekilde Ang II ve YG’un ERK1/2 MAPK fosforilasyonunu artırdığı bulundu.
SONUÇ: Ang II ve YG uygulanması VDKH’nde proliferasyonu 48 saat sonunda sinerjistik olarak artırır. NF-κB inhibisyonu VDKH’nde artmış proliferasyon ile sonuçlanabilir. Kanser ve inflamatuvar hastalıklar gibi farklı birçok alanda uygulama sahası bulan NF-κB inhibitörlerinin kullanımının aterosklerozda önemli rol oynayan VDKH proliferasyonu gibi istenmeyen etkileri olabileceği dikkate alınmalıdır.

Keywords

Anjiyotensin II, NF-κB, Proliferasyon, Vasküler düz kas hücresi, Yüksek glukoz

Thanks

Çalışma için herhangi bir yerden maddi destek alınmamıştır. Çalışma esnasındaki her türlü desteklerinden dolayı Prof. Dr. Akın Yeşilkaya’ya teşekkür ederim.

THE EFFECT OF ANGIOTENSIN II ON VASCULAR SMOOTH MUSCLE CELL PROLIFERATION IN HIGH GLUCOSE MEDIA

Abstract

OBJECTIVE: The main target of angiotensin II (Ang II) is vascular smooth muscle cell (VSMC) on the vascular wall. It contributes to atherosclerosis and hypertension pathogenesis by inducing the proliferation of these cells. Also, high glucose (HG) concentration contributes to accelerated atherosclerosis, observed in diabetics, by triggering the proliferation of these cells. However, studies those asserting an opposing argument are present. In this study, the aim was to determine the roles of Ang II and HG on VSMCs proliferation. To do this, Ang II’s effect on VSMC proliferation under low glucose (LG) or HG for 24, 48, and 72 hours was investigated. Moreover, p38 and ERK1/2 MAPKs and NF-κB roles in addition to the effects of AT1R inhibitors telmisartan and irbesartan were explored in Ang II-induced proliferation. Lastly, Ang II-induced ERK1/2 MAPK phosphorylation was determined to support proliferation data.
MATERIAL AND METHODS: Primary VSMCs isolated from rat aorta were used in the study. Proliferation was spectrophotometrically measured by using Wst-1 salt. ERK1/2 MAPK phosphorylation was determined by the western blot method.
RESULTS: The highest proliferation rate was observed at the end of 24 h when Ang II and HG were applied individually. It was observed that Ang II increased the proliferation approx. 1.7 times, and HG 1.5 times under LG media. Application of Ang II with HG yielded 25% more proliferation after 48 h. Telmisartan and irbesartan suppressed Ang II-induced augmented proliferation. Inhibition of NF-κB resulted in a dramatic increase in VSMCs proliferation. Inhibition of p38 and ERK1/2 MAPKs decreased proliferation. Finally, Ang II and HG alone enhanced ERK1/2 MAPK phosphorylation.
CONCLUSIONS: Ang II and HG treatment synergistically increase VSMC proliferation after 48 h. The inhibition of NF-κB might result in augmented VSMC proliferation. NF-κB inhibitors could be applied in different areas like cancer and inflammatory diseases, hence it should be noted that they could have undesired effects such as VSMC proliferation which plays an essential role in atherosclerosis.

Keywords

Angiotensin II, NF-κB, Proliferation, Vascular smooth muscle cell, High glucose

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