1 research outputs found
Feedback Response to Selective Depletion of Endogenous Carbon Monoxide in the Blood
The
physiological roles of endogenous carbon monoxide (CO) have not been
fully understood because of the difficulty in preparing a loss-of-function
phenotype of this molecule. Here, we have utilized in vivo CO receptors,
hemoCDs, which are the supramolecular 1:1 inclusion complexes of <i>meso</i>-tetrakis(4-sulfonatophenyl)porphinatoiron(II) with
per-<i>O</i>-methylated β-cyclodextrin dimers. Three
types of hemoCDs (hemoCD1, hemoCD2, and hemoCD3) that exhibit different
CO-affinities have been tested as CO-depleting agents in vivo. Intraperitoneally
administered hemoCD bound endogenous CO within the murine circulation,
and was excreted in the urine along with CO in an affinity-dependent
manner. The sufficient administration of hemoCD that has higher CO-affinity
than hemoglobin (Hb) produced a pseudoknockdown state of CO in the
mouse in which heme oxygenase-1 (HO-1) was markedly induced in the
liver, causing the acceleration of endogenous CO production to maintain
constant CO-Hb levels in the blood. The contents of free hemin and
bilirubin in the blood plasma of the treated mice significantly increased
upon removal of endogenous CO by hemoCD. Thus, a homeostatic feedback
model for the CO/HO-1 system was proposed as follows: HemoCD primarily
removes CO from cell-free CO-Hb. The resulting oxy-Hb is quickly oxidized
to met-Hb by oxidant(s) such as hydrogen peroxide in the blood plasma.
The met-Hb readily releases free hemin that directly induces HO-1
in the liver, which metabolizes the hemin into iron, biliverdin, and
CO. The newly produced CO binds to ferrous Hb to form CO-Hb as an
oxidation-resistant state. Overall, the present system revealed the
regulatory role of CO for maintaining the ferrous/ferric balance of
Hb in the blood