Araştırma Makalesi
BibTex RIS Kaynak Göster

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

Yıl 2022, Cilt: 23 Sayı: 4, 399 - 405, 17.10.2022
https://doi.org/10.18229/kocatepetip.929287

Öz

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.

Teşekkür

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

Kaynakça

  • 1. Eguchi S, Kawai T, Scalia R, et al. Understanding Angiotensin II Type 1 Receptor Signaling in Vascular Pathophysiology. Hypertension. 2018;71(5):804-10.
  • 2. St Paul A, Corbett CB, Okune R, et al. Angiotensin II, Hypercholesterolemia, and Vascular Smooth Muscle Cells: A Perfect Trio for Vascular Pathology. International Journal Of Molecular Sciences. 2020;21(12):4525.
  • 3. Shaw S, Wang X, Redd H, et al. High Glucose Augments the Angiotensin II-induced Activation of JAK2 in Vascular Smooth Muscle Cells via the Polyol Pathway. Journal of Biological Chemistry. 2003;278(33):30634-41.
  • 4. Won SM, Park YH, Kim HJ, et al. Catechins inhibit angiotensin II-induced vascular smooth muscle cell proliferation via mitogen-activated protein kinase pathway. Experimental & Molecular Medicine. 2006;38(5):525-34.
  • 5. Lavrentyev EN, Estes AM, Malik KU. Mechanism of High Glucose–Induced Angiotensin II Production in Rat Vascular Smooth Muscle Cells. Circulation Research. 2007;101(5):455-64.
  • 6. Kim YH, Han HJ. Synergistic effect of high glucose and ANG II on proliferation of mouse embryonic stem cells: involvement of PKC and MAPKs as well as AT1 receptor. Journal of Cellular Physiology. 2008;215(2):374-82.
  • 7. Wolf G, Wenzel U, Burns KD, et al. Angiotensin II activates nuclear transcription factor-kappaB through AT1 and AT2 receptors. Kidney International. 2002;61(6):1986-95.
  • 8. Hattori Y, Hattori S, Sato N,et al. High-glucose-induced nuclear factor kappaB activation in vascular smooth muscle cells. Cardiovascular Research. 2000;46(1):188-97.
  • 9. Li Y, Song Y-H, Mohler J, et al. Ang II induces apoptosis of human vascular smooth muscle via extrinsic pathway involving inhibition of Akt phosphorylation and increased FasL expression. American Journal of Physiology-Heart and Circulatory Physiology. 2006;290(5):2116-23.
  • 10. Wang J, Fu D, Senouthai S, et al. Critical roles of PI3K/Akt/NF‑κB survival axis in angiotensin II‑induced podocyte injury. Mol Med Rep. 2019;20(6):5134-44.
  • 11. Han X, Wang B, Sun Y, Huang J et al. Metformin Modulates High Glucose-Incubated Human Umbilical Vein Endothelial Cells Proliferation and Apoptosis Through AMPK/CREB/BDNF Pathway. Frontiers in Pharmacology. 2018;9:1266.
  • 12. Kırça M, Oğuz N, Çetin A, et al. Uric acid stimulates proliferative pathways in vascular smooth muscle cells through the activation of p38 MAPK, p44/42 MAPK and PDGFRβ. Journal of Receptors and Signal Transduction. 2017;37(2):167-73.
  • 13. Katakami N. Mechanism of Development of Atherosclerosis and Cardiovascular Disease in Diabetes Mellitus. J Atheroscler Thromb. 2018;25(1):27-39.
  • 14. Jiao L, Jiang M, Liu J, et al. Nuclear factor-kappa B activation inhibits proliferation and promotes apoptosis of vascular smooth muscle cells. Vascular. 2018;26(6):634-40.
  • 15. Yu C, Chen J, Guan W, et al. Activation of the D4 dopamine receptor attenuates proliferation and migration of vascular smooth muscle cells through downregulation of AT1a receptor expression. Hypertension Research. 2015;38(9):588-96.
  • 16. Dengfeng G, Xiaolin N, Ning N, et al. Regulation of Angiotensin II-Induced Krüppel-Like Factor 5 Expression in Vascular Smooth Muscle Cells. Biological & Pharmaceutical Bulletin. 2006;29:2004-8.
  • 17. Forrester SJ, Booz GW, Sigmund CD, et al. Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiological Reviews. 2018;98(3):1627-738.
  • 18. Yu KY, Wang YP, Wang LH, et al. Mitochondrial KATP channel involvement in angiotensin II-induced autophagy in vascular smooth muscle cells. Basic Research in Cardiology. 2014;109:416.
  • 19. Xi G, Shen X, Wai C, et al. Hyperglycemia induces vascular smooth muscle cell dedifferentiation by suppressing insulin receptor substrate-1– mediated p53/KLF4 complex stabilization. Journal of Biological Chemistry. 2019;294(7):2407-21.
  • 20. Zhou D-M, Ran F, Ni H-Z et al. Metformin inhibits high glucose-induced smooth muscle cell proliferation and migration. Aging (Albany NY). 2020;12(6):5352-61.
  • 21. Benson SC, Iguchi R, Ho CI, et al. Inhibition of cardiovascular cell proliferation by angiotensin receptor blockers: are all molecules the same? Journal of Hypertension. 2008;26(5):973-80.
  • 22. Yamamoto K, Ohishi M, Ho C, et al. Telmisartan-induced inhibition of vascular cell proliferation beyond angiotensin receptor blockade and peroxisome proliferator-activated receptor-gamma activation. Hypertension (Dallas, Tex : 1979). 2009;54(6):1353-9.
  • 23. Lu Q, Qiu T-Q, Yang H. Ligustilide inhibits vascular smooth muscle cells proliferation. European Journal of Pharmacology. 2006;542(1):136-40.
  • 24. Wang Y, Zhang X, Gao L et al. Cortistatin exerts antiproliferation and antimigration effects in vascular smooth muscle cells stimulated by Ang II through suppressing ERK1/2, p38 MAPK, JNK and ERK5 signaling pathways. Annals of Translational Medicine. 2019;7(20):561.
  • 25. Igarashi M, Wakasaki H, Takahara N, et al. Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J Clin Invest. 1999;103(2):185-95.
  • 26. Xu ZG, Kim KS, Park HC, et al. High glucose activates the p38 MAPK pathway in cultured human peritoneal mesothelial cells. Kidney International. 2003;63(3):958-68.
  • 27. Kırça M, Yeşilkaya A. Losartan inhibits EGFR transactivation in vascular smooth muscle cells. Turkish Journal of Medical Sciences. 2018;48(6):1364-71.
  • 28. Çağlar S, Çetin A, Uzuner F, et al. The role of AT1 receptor, Ras and NAD(P)H oxidase on p38 MAPK phosphorylation by angiotensin II stimulation in primary cultured vascular smooth muscle cells. Turk J Bioch. 2012;37(4):407-16.
  • 29. Montezano AC, Nguyen Dinh Cat A, Rios FJ, Touyz RM. Angiotensin II and Vascular Injury. Current Hypertension Reports. 2014;16(6):431.

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

Yıl 2022, Cilt: 23 Sayı: 4, 399 - 405, 17.10.2022
https://doi.org/10.18229/kocatepetip.929287

Öz

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.

Kaynakça

  • 1. Eguchi S, Kawai T, Scalia R, et al. Understanding Angiotensin II Type 1 Receptor Signaling in Vascular Pathophysiology. Hypertension. 2018;71(5):804-10.
  • 2. St Paul A, Corbett CB, Okune R, et al. Angiotensin II, Hypercholesterolemia, and Vascular Smooth Muscle Cells: A Perfect Trio for Vascular Pathology. International Journal Of Molecular Sciences. 2020;21(12):4525.
  • 3. Shaw S, Wang X, Redd H, et al. High Glucose Augments the Angiotensin II-induced Activation of JAK2 in Vascular Smooth Muscle Cells via the Polyol Pathway. Journal of Biological Chemistry. 2003;278(33):30634-41.
  • 4. Won SM, Park YH, Kim HJ, et al. Catechins inhibit angiotensin II-induced vascular smooth muscle cell proliferation via mitogen-activated protein kinase pathway. Experimental & Molecular Medicine. 2006;38(5):525-34.
  • 5. Lavrentyev EN, Estes AM, Malik KU. Mechanism of High Glucose–Induced Angiotensin II Production in Rat Vascular Smooth Muscle Cells. Circulation Research. 2007;101(5):455-64.
  • 6. Kim YH, Han HJ. Synergistic effect of high glucose and ANG II on proliferation of mouse embryonic stem cells: involvement of PKC and MAPKs as well as AT1 receptor. Journal of Cellular Physiology. 2008;215(2):374-82.
  • 7. Wolf G, Wenzel U, Burns KD, et al. Angiotensin II activates nuclear transcription factor-kappaB through AT1 and AT2 receptors. Kidney International. 2002;61(6):1986-95.
  • 8. Hattori Y, Hattori S, Sato N,et al. High-glucose-induced nuclear factor kappaB activation in vascular smooth muscle cells. Cardiovascular Research. 2000;46(1):188-97.
  • 9. Li Y, Song Y-H, Mohler J, et al. Ang II induces apoptosis of human vascular smooth muscle via extrinsic pathway involving inhibition of Akt phosphorylation and increased FasL expression. American Journal of Physiology-Heart and Circulatory Physiology. 2006;290(5):2116-23.
  • 10. Wang J, Fu D, Senouthai S, et al. Critical roles of PI3K/Akt/NF‑κB survival axis in angiotensin II‑induced podocyte injury. Mol Med Rep. 2019;20(6):5134-44.
  • 11. Han X, Wang B, Sun Y, Huang J et al. Metformin Modulates High Glucose-Incubated Human Umbilical Vein Endothelial Cells Proliferation and Apoptosis Through AMPK/CREB/BDNF Pathway. Frontiers in Pharmacology. 2018;9:1266.
  • 12. Kırça M, Oğuz N, Çetin A, et al. Uric acid stimulates proliferative pathways in vascular smooth muscle cells through the activation of p38 MAPK, p44/42 MAPK and PDGFRβ. Journal of Receptors and Signal Transduction. 2017;37(2):167-73.
  • 13. Katakami N. Mechanism of Development of Atherosclerosis and Cardiovascular Disease in Diabetes Mellitus. J Atheroscler Thromb. 2018;25(1):27-39.
  • 14. Jiao L, Jiang M, Liu J, et al. Nuclear factor-kappa B activation inhibits proliferation and promotes apoptosis of vascular smooth muscle cells. Vascular. 2018;26(6):634-40.
  • 15. Yu C, Chen J, Guan W, et al. Activation of the D4 dopamine receptor attenuates proliferation and migration of vascular smooth muscle cells through downregulation of AT1a receptor expression. Hypertension Research. 2015;38(9):588-96.
  • 16. Dengfeng G, Xiaolin N, Ning N, et al. Regulation of Angiotensin II-Induced Krüppel-Like Factor 5 Expression in Vascular Smooth Muscle Cells. Biological & Pharmaceutical Bulletin. 2006;29:2004-8.
  • 17. Forrester SJ, Booz GW, Sigmund CD, et al. Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiological Reviews. 2018;98(3):1627-738.
  • 18. Yu KY, Wang YP, Wang LH, et al. Mitochondrial KATP channel involvement in angiotensin II-induced autophagy in vascular smooth muscle cells. Basic Research in Cardiology. 2014;109:416.
  • 19. Xi G, Shen X, Wai C, et al. Hyperglycemia induces vascular smooth muscle cell dedifferentiation by suppressing insulin receptor substrate-1– mediated p53/KLF4 complex stabilization. Journal of Biological Chemistry. 2019;294(7):2407-21.
  • 20. Zhou D-M, Ran F, Ni H-Z et al. Metformin inhibits high glucose-induced smooth muscle cell proliferation and migration. Aging (Albany NY). 2020;12(6):5352-61.
  • 21. Benson SC, Iguchi R, Ho CI, et al. Inhibition of cardiovascular cell proliferation by angiotensin receptor blockers: are all molecules the same? Journal of Hypertension. 2008;26(5):973-80.
  • 22. Yamamoto K, Ohishi M, Ho C, et al. Telmisartan-induced inhibition of vascular cell proliferation beyond angiotensin receptor blockade and peroxisome proliferator-activated receptor-gamma activation. Hypertension (Dallas, Tex : 1979). 2009;54(6):1353-9.
  • 23. Lu Q, Qiu T-Q, Yang H. Ligustilide inhibits vascular smooth muscle cells proliferation. European Journal of Pharmacology. 2006;542(1):136-40.
  • 24. Wang Y, Zhang X, Gao L et al. Cortistatin exerts antiproliferation and antimigration effects in vascular smooth muscle cells stimulated by Ang II through suppressing ERK1/2, p38 MAPK, JNK and ERK5 signaling pathways. Annals of Translational Medicine. 2019;7(20):561.
  • 25. Igarashi M, Wakasaki H, Takahara N, et al. Glucose or diabetes activates p38 mitogen-activated protein kinase via different pathways. J Clin Invest. 1999;103(2):185-95.
  • 26. Xu ZG, Kim KS, Park HC, et al. High glucose activates the p38 MAPK pathway in cultured human peritoneal mesothelial cells. Kidney International. 2003;63(3):958-68.
  • 27. Kırça M, Yeşilkaya A. Losartan inhibits EGFR transactivation in vascular smooth muscle cells. Turkish Journal of Medical Sciences. 2018;48(6):1364-71.
  • 28. Çağlar S, Çetin A, Uzuner F, et al. The role of AT1 receptor, Ras and NAD(P)H oxidase on p38 MAPK phosphorylation by angiotensin II stimulation in primary cultured vascular smooth muscle cells. Turk J Bioch. 2012;37(4):407-16.
  • 29. Montezano AC, Nguyen Dinh Cat A, Rios FJ, Touyz RM. Angiotensin II and Vascular Injury. Current Hypertension Reports. 2014;16(6):431.
Toplam 29 adet kaynakça vardır.

Ayrıntılar

Birincil Dil Türkçe
Konular Klinik Tıp Bilimleri
Bölüm Makaleler-Araştırma Yazıları
Yazarlar

Mustafa Kırça 0000-0002-2959-1735

Yayımlanma Tarihi 17 Ekim 2022
Kabul Tarihi 18 Aralık 2021
Yayımlandığı Sayı Yıl 2022 Cilt: 23 Sayı: 4

Kaynak Göster

APA Kırça, M. (2022). ANJİYOTENSİN II’NİN YÜKSEK GLUKOZLU ORTAMDA VASKÜLER DÜZ KAS HÜCRE PROLİFERASYONUNA ETKİSİ. Kocatepe Tıp Dergisi, 23(4), 399-405. https://doi.org/10.18229/kocatepetip.929287
AMA Kırça M. ANJİYOTENSİN II’NİN YÜKSEK GLUKOZLU ORTAMDA VASKÜLER DÜZ KAS HÜCRE PROLİFERASYONUNA ETKİSİ. KTD. Ekim 2022;23(4):399-405. doi:10.18229/kocatepetip.929287
Chicago Kırça, Mustafa. “ANJİYOTENSİN II’NİN YÜKSEK GLUKOZLU ORTAMDA VASKÜLER DÜZ KAS HÜCRE PROLİFERASYONUNA ETKİSİ”. Kocatepe Tıp Dergisi 23, sy. 4 (Ekim 2022): 399-405. https://doi.org/10.18229/kocatepetip.929287.
EndNote Kırça M (01 Ekim 2022) ANJİYOTENSİN II’NİN YÜKSEK GLUKOZLU ORTAMDA VASKÜLER DÜZ KAS HÜCRE PROLİFERASYONUNA ETKİSİ. Kocatepe Tıp Dergisi 23 4 399–405.
IEEE M. Kırça, “ANJİYOTENSİN II’NİN YÜKSEK GLUKOZLU ORTAMDA VASKÜLER DÜZ KAS HÜCRE PROLİFERASYONUNA ETKİSİ”, KTD, c. 23, sy. 4, ss. 399–405, 2022, doi: 10.18229/kocatepetip.929287.
ISNAD Kırça, Mustafa. “ANJİYOTENSİN II’NİN YÜKSEK GLUKOZLU ORTAMDA VASKÜLER DÜZ KAS HÜCRE PROLİFERASYONUNA ETKİSİ”. Kocatepe Tıp Dergisi 23/4 (Ekim 2022), 399-405. https://doi.org/10.18229/kocatepetip.929287.
JAMA Kırça M. ANJİYOTENSİN II’NİN YÜKSEK GLUKOZLU ORTAMDA VASKÜLER DÜZ KAS HÜCRE PROLİFERASYONUNA ETKİSİ. KTD. 2022;23:399–405.
MLA Kırça, Mustafa. “ANJİYOTENSİN II’NİN YÜKSEK GLUKOZLU ORTAMDA VASKÜLER DÜZ KAS HÜCRE PROLİFERASYONUNA ETKİSİ”. Kocatepe Tıp Dergisi, c. 23, sy. 4, 2022, ss. 399-05, doi:10.18229/kocatepetip.929287.
Vancouver Kırça M. ANJİYOTENSİN II’NİN YÜKSEK GLUKOZLU ORTAMDA VASKÜLER DÜZ KAS HÜCRE PROLİFERASYONUNA ETKİSİ. KTD. 2022;23(4):399-405.

88x31.png
Bu Dergi Creative Commons Atıf-GayriTicari-AynıLisanslaPaylaş 4.0 Uluslararası Lisansı ile lisanslanmıştır.