HIF-1α is required for disturbed flow-induced metabolic reprogramming in human and porcine vascular endothelium

نویسندگان

  • David Wu
  • Ru-Ting Huang
  • Robert B Hamanaka
  • Matt Krause
  • Myung-Jin Oh
  • Cheng-Hsiang Kuo
  • Recep Nigdelioglu
  • Angelo Y Meliton
  • Leah Witt
  • Guohao Dai
  • Mete Civelek
  • Nanduri R Prabhakar
  • Yun Fang
  • Gökhan M Mutlu
چکیده

Hemodynamic forces regulate vascular functions. Disturbed flow (DF) occurs in arterial bifurcations and curvatures, activates endothelial cells (ECs), and results in vascular inflammation and ultimately atherosclerosis. However, how DF alters EC metabolism, and whether resulting metabolic changes induce EC activation, is unknown. Using transcriptomics and bioenergetic analysis, we discovered that DF induces glycolysis and reduces mitochondrial respiratory capacity in human aortic ECs. DF-induced metabolic reprogramming required hypoxia inducible factor-1α (HIF-1α), downstream of NAD(P)H oxidase-4 (NOX4)-derived reactive oxygen species (ROS). HIF-1α increased glycolytic enzymes and pyruvate dehydrogenase kinase-1 (PDK-1), which reduces mitochondrial respiratory capacity. Swine aortic arch endothelia exhibited elevated ROS, NOX4, HIF-1α, and glycolytic enzyme and PDK1 expression, suggesting that DF leads to metabolic reprogramming in vivo. Inhibition of glycolysis reduced inflammation suggesting a causal relationship between flow-induced metabolic changes and EC activation. These findings highlight a previously uncharacterized role for flow-induced metabolic reprogramming and inflammation in ECs.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Letter by Wu et al Regarding Article, "Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites".

Letter by Wu et al Regarding Article, “Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites” To the Editor: We read with interest the recent article “Mechanical Activation of Hypoxia-Inducible Factor 1α Drives Endothelial Dysfunction at Atheroprone Sites” in which Feng et al elegantly show that exposure of endothelial cells to mechanical low s...

متن کامل

Exercise-induced expression of angiogenesis-related transcription and growth factors in human skeletal muscle.

mRNA expression of vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and hypoxia-inducible factor (HIF) subunits HIF-1α and HIF-1β in human skeletal muscle was studied during endurance exercise at different degrees of oxygen delivery. Muscle biopsies were taken before and after 45 min of one-legged knee-extension exercise performed under conditions of nonrestricted ...

متن کامل

A novel resveratrol analogue, HS-1793, inhibits hypoxia-induced HIF-1α and VEGF expression, and migration in human prostate cancer cells.

In many studies, resveratrol has been shown to have a chemopreventive effect in various types of cancer cells. However, the biological activity of resveratrol is limited by its photosensitivity and metabolic instability. This study investigated the effects of a novel analogue of resveratrol, HS-1793, on the expression of HIF-1α and vascular endothelial growth factor (VEGF) in PC-3 human prostat...

متن کامل

Human cytomegalovirus encoded chemokine receptor US28 activates the HIF-1α/PKM2 axis in glioblastoma cells

The human cytomegalovirus (HCMV) encoded chemokine receptor US28 promotes tumorigenesis through activation of various proliferative and angiogenic signaling pathways. Upon infection, US28 displays constitutive activity and signals in a G protein-dependent manner, hijacking the host's cellular machinery. In tumor cells, the hypoxia inducible factor-1α/pyruvate kinase M2 (HIF-1α/PKM2) axis plays ...

متن کامل

Normal glucose uptake in the brain and heart requires an endothelial cell-specific HIF-1α-dependent function.

Although intimately positioned between metabolic substrates in the bloodstream and the tissue parenchymal cells that require these substrates, a major role of the vascular endothelium in the regulation of tissue metabolism has not been widely appreciated. We hypothesized that via control of transendothelial glucose transport and contributing paracrine mechanisms the endothelium plays a major ro...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 6  شماره 

صفحات  -

تاریخ انتشار 2017