Prolyl-4-hydroxylase inhibition

Siddiq, A., Ayoub, I.A., Chavez, J.C., et al. (2005) Hypoxia-inducible factor prolyl 4-hydroxylase inhibition. A target for neuroprotection in the central nervous system. J. Biol. Chem., 280,41732-41743. 

Hsieh, M.M., Linde, N.S.,Wynter,A., eta/. (2007) HIF prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques. Blood, 110, 2140-2147. 

Gottlieb E. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 114. 2005 7 77-85. 

Ivan M, Haberberger T, Gervasi DC, Michelson KS, Giinzler V, Kondo K, Yang H, Sorokina I, Conaway RC, Conaway JW, Kaelin WG. Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor. Proc. Natl. Acad. Sci. U.S.A. 2002 99 13459-13464. 

Table I. Effect of Silicic Acid on Inhibition of Prolyl-hydroxylase by Aluminum...

Apart from being a cofactor of prolyl and lysyl hydroxylase, ascorbate affects the hydroxylation of procollagen at various levels of regulation. It activates a silent form of prolyl hydroxylase (Mussini et al., 1961 Stassen et al, 1973 Hayaishi et al, 1975 Cardinale et al, 1975) and may also increase the enzyme levels by transcriptional activation and translational events (Qian et al, 1993). Interestingly, all these regulatory interventions appear to be linked to the redox properties, i.e., the prooxidant potential of ascorbate. The activation of the inactive form of prolyl hydroxylase is reversed by dithiothreitol (Hayaishi et al, 1975) and the induction of its biosynthesis appears to be mediated by the superoxide ion, which activates an epigenetic control mechanism involving poly ADP-ribose the induction of prolyl hydroxylase by ascorbate is prevented by both addition of superoxide dismutase and inhibition of poly ADP-ribose synthetase (Qian et al, 1993). 

Metzen, E., Zhou, J., Jelkmann, W., Fandrey, J., and Brune, B. (2003). Nitric oxide impairs nor-moxic degradation of HIF-lalpha by inhibition of prolyl hydroxylases. Mol. Biol. Cell 14, 3470-3481. 

Molidustat (BAY 85-3934) is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH), which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO [136]. Molidustat is currently under clinical trials at Bayer for the treatment of patients suffering from renal anemia due to chronic kidney disease. 

Figure 3.4 Factors affecting foreign body reaction and potential points of intervention at the level of the myofibroblast (1) inhibit synthesis or release of TGF-P (2) block stimulation by TGF-P of its membrane receptors on the activated fibroblast (3) inhibit the Smad proteins, which transfer the TGF-P effect to the nucleus (4) inhibit transcription of procollagen mRNA (5) inhibit translation of the message to form procollagen (6) inhibit prolyl-4-hydroxylase, which creates hydroxyproline and facilitates helix formation (7) inhibit lysyl oxidase, which cross-links the collagen (8) enhance the function of MMPs, which degrade collagen, or inhibit TIMPs, which degrade MMPs.

Kim I, Mogford JE, Witschi C, Nafissi M, Mustoe TA. Inhibition of prolyl 4-hydroxylase reduces scar hypertrophy in a rabbit model of cutaneous scarring. Wound Repair and Regeneration 2003, 11, 368-372. 

Y. Matsumura, I. Sakaida, K. Uchida, T. Kimura, T. Ishihara, and K. Okita, Prolyl 4-hydroxylase inhibitor (HOE 077) inhibits pig serum-induced rat fiver fibrosis by preventing stellate cell activation, J. Hepatol. 27 185-192 (1997). 

Nwogu Jl, Geenen D, Bean M, Brenner MC, Huang X, Buttrick PM. Inhibition of collagen synthesis with prolyl 4-hydroxylase inhibitor improves left ventricular function and alters the pattern of left ventricular dilatation after myocardial infarction. Circulation 2001 104 2216-2221. 

A representation of hypoxia-inducible factor (HIF) function. In normoxia, HIF Ia is broken down after prolyl hydroxylation and its interaction with p300 is diminished after aspargyl hydroxylation. In hypoxia, hydroxylase enzymes are inhibited, whereby the DNA binding of HIF may occur and oxygen-sensitive genes can be induced... 

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