1. OXYGEN SENSING, HOMEOSTASIS, AND DISEASE SEMENZA. NEJM, AUGUST 2011, 246: 6 Amelia Crawford PA-S2

2. Hypoxia Inducible Factor 1  All nucleated cells in the human body respond to hypoxia  HIF-1 plays a critical role in the cells’ response.  When oxygen availability is decreased, HIF-1 regulates the expression of genes that mediate adaptive responses by cells

3. Hypoxia Inducible Factor 1  HIF-1 is composed of a beta and an alpha subunit.  The alpha subunit is oxygen regulated  In aerobic conditions, HLF-1 (alpha) is normally hydroxylated and then degraded by proteasomes  In hypoxic conditions, the hydroxylation is inhibited, HIF-1 (alpha) accumulates, and it up regulates several genes to promote survival in cells  Stimulates erythropoetin, angiogenesis, & glycolytic metabolism

4. HIF-1

5. HIF-1 and Cardiovascular Disease  Atherosclerotic disease causes stenosis of vessels and results in decreased blood flow distally.  Decreased blood flow → decreased O2 supply  In studies with mice in which the femoral artery was ligated, induction of HIF-1 resulted in increased activation of VEGF, which eventually caused angiogenesis and reperfusion of the limb via the production of collateral blood flow.  The normal adaptive vascular response is impaired by aging & DM—major causes of CAD and PVD

6. HIF-1 and Cardiovascular Disease  VEGF other factors promote angiogenesis by stimulating vascular cells and also by mobilizing bone-marrow derived angiogenic cells (BMDACs)  BMDACs = myeloid cells that stimulate vascular remodeling.  In order to initiate a vascular response, they must mobilized from bone marrow, enter the peripheral blood, and be retained within the ischemic tissue by adhering to the vascular endothelium.  Aging results in the loss of ischemia induced expression of angiogenic factors and BMDAC mobilization and consequently, angiogenesis and reperfusion are decreased.

7. HIF-1 and Cardiovascular Disease  HIF-1 α induction occurs early in the course of a MI  In studies with mice with an over expression of HIF-1 α that underwent coronary artery ligation, there was a smaller infarct size, improved cardiac function, and increased capillary density.  Collateral vessels are routinely identified in 2/3 of patients with critical coronary artery disease that is sufficient to cause angina.  Patients with a collateral blood supply that eventually suffered a MI also had smaller infarcts and were more likely to survive than those without a collateral vessels.  HIF-1 also helps the heart to survive episodes of O2 deprivation by inducing glycolytic metabolism & adenosine production

8. HIF-1 and Cardiovascular Disease  Pharmacologic agents that activate HIF-1 are a therapeutic target in treating patients with CAD and PVD (Gene therapy)  In preclinical trials, patients with CAD or PVD were given a recombinant adenovirus that encoded for a protein that contained the terminal half of HIF-1 alpha gene fused to an activator protein.  It was administered either via an IM injection (PVD) or intramyocardial injections (CAD) prior to CABG  No adverse effects were seen but also no reports of efficacy were released. This could be due to the fact that the protein did not contain all of the HIF-1 alpha gene and in turn did not encode for all the activities of the gene.

9. HIF-1 and Cardiovascular Disease  Another pharmacologic alternative for targeting HIF-1 in cardiovascular disease is the development of drugs that inhibit the hydroxylation of HIF-1.  These drugs either:  1. chelate Fe, (Fe is present in the center of the hydroxylases) or  2. compete with the hydroxylases at the binding site

10. HIF-1 and Cardiovascular Disease  A final alternative would be the use of HIF target gene products as therapeutic agents.  Already been done via cloning of erythropoietin gene and production of recombinant human erythropoietin.  Used in chronic renal failure patients to stimulate RBC production  However administration of a single angiogenic factor such as VEGF fails to stimulate a vascular response.  Benefit of using downstream proteins as therapeutic agents is that they act immediately whereas gene therapy requires more time for trascription and translation of target gene products.

11. HIF-1 and Cancer  In cancer the physiologic responses to hypoxia aids in disease progression  Tumor vessels are structurally & functionally abnormal and contain areas of severe hypoxia.  This results in HIF-1 over expression, which causes additional angiogenesis, genetic instability, immune evasion, metabolic reprogramming, and invasion, and metastasis.

12. HIF-1 and Cancer  Hypoxia within the tumor is a major mechanism that activates HIF-1  Loss of tumor suppressor function or increased oncogene function also activates HIF-1.  HIF-1 regulates a myriad of target genes  However, only a small subset of genes in any given cancer will be regulated by HIF-1  The role of HIF-1 in a specific cancer can guide possible therapies.

13. HIF-1 and Cancer  A number of chemotherapy agents are directed at inhibiting HIF-1  Topotecan  Also cardiac glycosides like Digoxin have been shown to decrease HIF-1 and subsequent tumor growth in mice.  Others are agents aimed at blocking HIF-1 are being investigated

14. HIF-1 and Pulmonary Hypertension  Pulmonary hypertension is a progressive and often fatal consequence of chronic lung disease  In contrast to systemic arterioles which dilate in order to increase tissue perfusion during hypoxia, pulmonary arterioles constrict to shunt blood away from areas of the lung that are not ventilated  This eventually leads to cor pulmonale and progressive hypoxemia.

15. HIF-1 and Pulmonary Hypertension  HIFs regulate target genes that play major roles in the pathology of pulmonary HTN.  Alveolar hypoxia induces HIF-1 activity in vascular smooth muscle cells and alters the intracellular concentrations of K, Ca, & H ions  This leads to smooth muscle cell hypertrophy, proliferation, depolarization, & contraction and increased pulmonary vascular resistance

16. HIF-1 and Pulmonary Hypertension  Tibetans live in conditions of chronic hypoxia & they have blunted responses to hypoxia, which prevents the development of pulmonary hypertension.  Gene sequencing has revealed loci encoding HIF-2 α, hyroxylases (PHD2), factor inhibiting HIF-1, and HIF target genes as playing a significant role in the adaptation that Tibetans exhibit.  Alters vascular, erythropoeitic, and metabolic responses to hypoxia

17. Conclusions  HIF-1 is an adaptive response in cardiovascular and peripheral vascular disease  HIF-1 is mal-adaptive in cancer  HIF-1 is also maladaptive in chronic lung disease and pulmonary hypertension.  The targeting of HIFs and its inhibitors and activators offer possible treatment options of these diseases.