Carbon Monoxide and Cardiovascular Function

Bob Johnson
robertj393@aol.com

>(1) Since CO can freely across membrane, CO might just be produced in vascular smooth muscle cells and permeat to endothelial cell. There CO affects NOS system. What's your view on this modified model?

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Dr. Wang, you raise an interesting and important point. Carbon monoxide which is generated in the vascular smooth muscle compartment should, I guess, potentially diffuse into the endothelium. However carbon monoxide generated within the endothelium (providing that heme oxygenase is present in that endothelial bed) should have a higher probability of effecting the proximally located nitric oxide synthase co-localized within the endothelium.

We attempted to simplify a potentially confusing theoretical point, by minimizing the diagram for the presentation to highlight the latter... but the addition of your modification certainly seems plausible.


>(2) What could be the physiological stimuli that selectively activate endothelial HO or smooth muscle HO? A more generalized question is what can act as the endogenous factor to release CO?

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In short, we don't know.

But, if you are asking for speculation:

I think we need to distinguish between chronic and acute manipulations of the heme-heme oxygenase-carbon monoxide system. Certainly, heme oxygenase can be chronically induced. This induction is also certainly accompanied by increased generation of heme oxygenase products.

Acutely, stearic modification and/or perhaps NADPH and/or other co-factor availability might drive the formation of heme-derived carbon monoxide.  Such possibilities seem viable. Also, perhaps endogenously formed heme-related metalloporphyrins may acutely compete with heme for binding to the heme oxygenase in vivo. In addition, the biliverdin product might also play some in vivo role to alter heme oxygenase activity.

From our in vivo and in vitro acute manipulations, we have become very confident that heme oxygenase products can be rapidly promoted by providing heme. Accordingly, I think that we should also seriously consider the possibility that heme availability, and its regulation at the level of dALA synthase activity and/or in some cases at the level of ferrochelatase activity may also constitute important regulatory points for heme oxygenase-mediated formation of carbon monoxide.

Of particular regulatory importance in the endothelium compartment may be the ferrochelatase, the enzyme which "inserts" the iron into the porphyrin ring as the last step in the formation of new heme.  Biochemical studies have strongly suggested that nitric oxide can inhibit ferrochelatase activity (Sellers et al, Biochemistry, 55:2699-2704, 1996). Such a mechanism might allow for differential acute regulation of the HO preferentially in the endothelium over that in the smooth muscle domain.

But again, these are just speculations.....