I have 25 years of experience studying the enzymology of 2-oxoglutarate-dependent dioxygenases, such as the collagen P4Hs and the hypoxia-inducible factor (HIF) P4Hs. We were the first to show that the HIF-P4Hs have a very low affinity for oxygen making these enzymes cellular oxygen sensors. We were also the first to characterize in detail their catalytic and inhibitory properties which laid the basis for the development of HIF-P4H inhibitors aimed for therapeutic applications, such as for the treatment of anemia. During recent years I have extended my research to study the role and regulation of the hypoxia response pathway in vivo. We have generated a unique mouse line which has continuos activation of the hypoxia response and has allowed us to study the effects of long-term activation of this pathway. We were the first to show that such mice are protected against cardiac and skeletal muscle ischemia. We recently reported ground breaking discoveries that these mice are also protected from obesity, metabolic dysfunction and atherosclerosis, and importantly, this protection was also demonstrated in wild-type mice treated with a pharmacologic HIF-P4H inhibitor.
Dana-Farber Cancer Institute, Harvard Medical School