Table 1.

Impact of prolyl-hydroxylase domain (PHD), hypoxia-inducible factor (HIF), factor inhibiting HIF (FIH), and von Hippel-Lindau gene (VHL) mutations on cellular and tissue function.

Mouse Models
Gene	Outcome	Publication
PHD1	Knockout (KO) protects from I/R injury in the liver and heart, reducing size of infarction and increasing scavenging of oxygen radicals, and protects against ischemic stroke	Schneider, M.; et al. Gastroenterology 2010 [28]
		Adluri, R.S.; et al. Antioxid. Redox Signal 2011 [29]
		Quaegebeur, A.; et al. Cell Metab. 2016 [30]
	Metabolic disturbance; KO promotes liver steatosis and insulin resistance, with increased glycolysis; attenuated hypercholesterolemia and hyperglycemia	Thomas, A.; et al. Sci. Rep. 2016 [31]
		Marsch, E.; et al. Eur. Heart J. 2016 [32]
	KO increases capillary and arteriolar density in response to ischemia	Rishi, M.T.; et al. Microvasc. Res. 2015 [33]
	KO increases hepatocyte proliferation and liver regeneration	Mollenhauer, M.; et al. Langenbeck’s Arch. Surg. 2012 [34]
PHD2	Conditional knockout (CKO) leads to increased angiogenesis and angiectasia	Takeda, K.; et al. Circulation 2007 [35]
	CKO increases EPO levels and erythropoiesis	Takeda, K.; et al.; Blood 2008 [36]
	CKO in EPO-producing cells leads to decreased bone density, while CKO in chondrocytes leads to increased bone density	Rauner, M.; et al. J. Bone Miner. Res. 2016 [37]
		Cheng, S.; et al. Endocrinology 2016 [38]
	PHD2 erythrocytosis	Arsenault, P.R.; et al. J. Biol. Chem. 2013 [39]
		Franke, K.; et al. Blood 2013 [40]
PHD3	KO leads to increased angiogenesis, with increased cardiac function and decreased fibrosis after ischemic injury	Oriowo, B.; et al. Curr. Pharm. Des. 2014 [41]
		Xie, L.; et al. J. Mol. Cell. Cardiol. 2015 [42]
	Regulation of neuronal apoptosis; dysregulation of sympathoadrenal development	Bishop, T.; et al. Mol. Cell. Biol. 2008 [43]
	KO leads to decreased neuronal apoptosis but decreased sympathoadrenal function	Taniguchi, C.M.; et al. Nat. Med. 2013 [44]
	Knockdown in glioblastoma cells and KO in astrocytoma cells; increased tumor growth	Henze, A.T.; et al. Nat. Commun. 2014 [45]
FIH-1	KO causes decreased weight, increased metabolic rate, resistance to hepatic steatosis, and high fat diet-induced weight gain (occurs also with KO in neuronal cells)	Zhang, N.; et al. Cell Metab. 2010 [46]
HIF2A	HIF2A erythrocytosis	Tan, Q.; et al. J. Biol. Chem. 2013 [47]
Human Mutations
PHD2	Mutation causing decreased function causes congenital erythrocytosis	Percy, M.J.; et al. Proc. Natl. Acad. Sci. USA 2006 [48]
HIF2A	Mutation decreasing binding to PHD2 and VHL causes erythrocytosis	Van Wijk, R.; et al. Haematologica 2010 [49]
		Percy, M.J.; et al. NEJM 2008 [50]
VHL	Germline loss-of-function in VHL leading to erythrocytosis	Gordeuk; et al. Blood 2011 [51]

CKO: conditional knockout; I/R: ischemic/reperfusion; EPO: erythropoietin; KO: knockout.