Effects of the Hypoxia Response on Metabolism in Atherosclerosis and Pregnancy

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

Kontinkangas Campus, lecture hall F101

Topic of the dissertation

Effects of the Hypoxia Response on Metabolism in Atherosclerosis and Pregnancy

Doctoral candidate

Licentiate of Medicine Jenni Määttä

Faculty and unit

University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, Hypoxia response

Subject of study

Biochemistry and molecular medicine

Opponent

Adjunct Professor Heikki Koistinen, University of Helsinki

Custos

Professor Peppi Karppinen, University of Oulu

Add event to calendar

Metabolic effects of oxygen defiency in atherosclerosis and pregnancy

Oxygen is vital for human survival. When oxygen is lacking, a state of hypoxia occurs, and adaptive changes in gene expression increase oxygen delivery to promote survival. The key regulator of the transcriptional hypoxia response is hypoxia-inducible factor (HIF) which targets over 1000 genes. The HIF prolyl 4-hydroxylases (HIF-P4Hs) govern the stability of HIF in an oxygen-dependent fashion. In our studies we investigated whether activation of the hypoxia response through inhibition of either of two distinct HIF-P4Hs, HIF-P4H-2 or P4H-TM would reduce atherosclerosis in mice.

We found that inhibition of HIF-P4H-2 led to reductions in numbers of atherosclerotic plaques, and levels of serum cholesterol and inflammation in white adipose tissue and aortic plaques. In addition, HIF-P4H-2 deficient mice had elevated levels of modified LDL-targeting, atheroprotective circulating autoantibodies. The P4H-TM knockout mice also had reduced numbers of atherosclerotic plaques and increased levels of atheroprotective autoantibodies in their sera, but in contrast to the HIF-P4H-2 deficient mice, they also showed a reduction in serum triglyceride levels.

To determine how hypoxia alters maternal glucose and lipid metabolism in pregnancy, we studied pregnant mice that were predisposed to a hypoxic condition (15% ambient O2). We found that they had enhanced glucose metabolism due to reduced insulin resistance and an increased flux of glucose to maternal tissues. The hypoxic dams also failed to gain weight and store adipose tissue in the anabolic phase to the same extent as normoxic control dams.

These results implicate HIF-P4H inhibition as a novel therapeutic mechanism for atherosclerosis, and suggest that the small molecule HIF-P4H inhibitors currently in clinical trials for renal anemia may have further possible therapeutic applications. In addition, greater understanding of the changes in maternal metabolism that underly reduced fetal growth in hypoxic conditions, and the development of targeted interventions may allow the preservation of fetal growth in cases of maternal hypoxia
Last updated: 17.5.2019