Diyabetik Kardiyomiyopati ve Prolil Hidroksilazlar

Diyabetik kardiyomiyopati (DKMP), diyabet hastalarında koroner arter hastalığı ve hipertansiyondan bağımsız olarak geli?en ventriküler disfonksiyon olarak ifade edilmektedir. Kalp dokusunda görülen, intersitisyal fibrozis, miyosit hipertrofisi ve artmı? kontraktil protein glikozilasyonu DKMP'de görülen kardiyak patolojilere örnek te?kil eder. Sistolik disfonksiyon DKMP'de genellikle geç ve belirgin diyastolik disfonksiyonu olan hastalarda görülen bir bulgudur. DKMP'nin birçok ba?lıktan olu?an oldukça karma?ık bir patofizyolojisi vardır. Bu derlemede prolil hidroksilazların da içerisinde bulunduğu HIF-VEGF-anjiyogenez aksındaki bozulmalar üzerinde yoğunla?ılmı?tır. Diyabette hipoksiye verilen HIF yanıtının bozulduğu ve bu deği?imin DKMP'nin patogenezinde önemli bir yer tuttuğu bilinmektedir. Prolil hidroksilazlar (PHD'ler), moleküler oksijeni kofaktör olarak kullanan, oksijen varlığında HIF-? (hipoksi ile indüklenen faktör-?) altbirimini degrade eden enzim yapılı moleküllerdir. Hücresel oksijen homeostazında ve hipoksiye verilen HIF cevabında önemli bir yere sahiptirler. Hipoksik ko?ullarda PHD enzimi inaktif hale gelir ve degradasyondan kurtulan HIF-1?, ? alt birimi ile birle?erek HIF-1 molekü- lünü olu?turur. 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 çalı?ma bulunmaktadır. Diyabette PHD merkezli ara?tırmaların artması diyabette önleyici ve tedavi edici stratejilerin geli?tirilmesi açısından önemli bilgiler üretilmesine açık bir alandır.

Diabetic Cardiomyopathy and Prolyl Hydroxylases

Diabetic cardiomyopaty (DCMP) is described as ventricular dysfunction seen in diabetic patientswhich manifests itself without any coronary artery disease and hypertension. One may observe intersititialfibrosis, myocyte hypertrophy and contractile protein glycation in DCMP. Diastolic dysfunctionis the earliest and most of the time only symptom of DCMP. Generally systolic dysfunction is a latesymptom which is seen in patients who have significant diastolic dysfunction.DCMP has a very complex pathophysiology which can be indexed in many titles. We focused on HIFVEGF-Angiogenesisaxis which contains prolyl hydroxilases. In diabetes HIF response to hypoxia isblunted and it is known that this alteration is an important contributor to DCMP prognosis.Prolyl hydroxilases are enzymatic molecules (PHDs) which, uses molecular oxygen as cofactor and ifoxygen is abundant they degrade HIF-α (hypoxia induced factor-α) subunit. They have an importantrole in cellular oxygen homeostasis and HIF response to hypoxia. In hypoxic conditions, PHD becomesinactive that saves HIF-1α from degradation and HIF-1α unites with β subunit to form HIF-1 molecule.This phenomenon is named as “HIF stabilisation”. Stabilised HIF-1 molecule modifies lots of protein’stranscription rate in the cell. Activation of HIF’s downstream targets, lowers the energy and oxygenconsumption and increases the delivery of oxygen to the cell which protects the cell from hypoxicdamage.The genomic profile generated with HIF activation has cardioprotective effect in DCMP. HIF overexpressinggenetic models, hypoxia application, PHD inhibitors and PHD silencing methods is usedto activate HIF system.There are limited number of studies in literature about the effect of diabetes on PHDs. Increment ofPHD-based research in diabetes may help the production of valuable knowledge about preventiveand therapeutical strategies in diabetes.

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