Diyabetik Kardiyomiyopati ve Prolil Hidroksilazlar

Year 2017, , 29 - 36, 21.04.2017

Fırat Akat

https://doi.org/10.1501/Tipfak_0000000961

Abstract

Diyabetik kardiyomiyopati (DKMP), diyabet hastalarında koroner arter hastalığı ve hipertansiyondan bağımsız olarak gelișen ventriküler disfonksiyon olarak ifade edilmektedir. Kalp dokusunda görülen, intersitisyal fibrozis, miyosit hipertrofisi ve artmıș kontraktil protein glikozilasyonu DKMP’de görülen kardiyak patolojilere örnek teșkil eder. Sistolik disfonksiyon DKMP’de genellikle geç ve belirgin diyastolik disfonksiyonu olan hastalarda görülen bir bulgudur.

DKMP’nin birçok bașlıktan olușan oldukça karmașık bir patofizyolojisi vardır. Bu derlemede prolil hidroksilazların da içerisinde bulunduğu HIF-VEGF-anjiyogenez aksındaki bozulmalar üzerinde yoğunlașılmıștır. Diyabette hipoksiye verilen HIF yanıtının bozulduğu ve bu değișimin DKMP’nin patogenezinde önemli bir yer tuttuğu bilinmektedir.

Prolil hidroksilazlar (PHD’ler), moleküler oksijeni kofaktör olarak kullanan, oksijen varlığında HIF-α (hipoksi ile indüklenen faktör-α) altbirimini degrade eden enzim yapılı moleküllerdir. Hücresel oksijen homeostazında ve hipoksiye verilen HIF cevabında önemli bir yere sahiptirler. Hipoksik koșullarda PHD enzimi inaktif hale gelir ve degradasyondan kurtulan HIF-1α, β alt birimi ile birleșerek HIF-1 molekülünü olușturur. Bu olaya “HIF stabilizasyonu” adı verilir. Stabilize olan HIF-1 molekülü hücredeki birçok proteinin transkripsiyonunu modifiye eder. HIF’in alt hedeflerinin aktivasyonu hücrenin enerji ve oksijen tüketimini azaltır ve hücreye oksijen arzını arttırır, böylece hipoksik sürecin en az hasarla atlatılması sağlanır.

HIF aktivasyonu sonucu açığa çıkan genomik profilin DKMP’de koruyucu etkileri olduğu bilinmektedir. HIF sistemini aktive etmek için HIF overekspresyonu yapılan genetik modeller, hipoksi uygulaması, PHD inhibitörleri ve PHD geninin susturulması gibi yöntemler kullanılmaktadır.

Literatürde diyabetin PHDlere olan etkisi ile ilgili az sayıda çalıșma bulunmaktadır. Diyabette PHD merkezli araștırmaların artması diyabette önleyici ve tedavi edici stratejilerin geliștirilmesi açısından önemli bilgiler üretilmesine açık bir alandır. 

Keywords

Diyabetik Kardiyomiyopati, Prolil hidroksilazlar, Hipoksi

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