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Protoporphyrin IX Generation from ä‐Aminolevulinic Acid Elicits Pulmonary Artery Relaxation and Soluble Guanylate Cyclase Activation
Author(s) -
Mingone Christopher J.,
Gupte Sachin A.,
Chow Joseph L.,
Abraham Nader G.,
Wolin Michael S.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a400-d
Subject(s) - gucy1a3 , guanylate cyclase , gucy1b3 , protoporphyrin ix , gucy2d , chemistry , guanylate cyclase 2c , pulmonary artery , medicine , relaxation (psychology) , cardiology , biochemistry , enzyme , organic chemistry , photodynamic therapy
Protoporphyrin IX (PpIX) has been shown to be an activator of soluble guanylate cyclase (sGC), but, its role as an endogenous regulator of vascular function through cGMP has not been reported previously. In this study we examined if the heme precursor ä‐aminolevulinic acid (ALA) could regulate vascular force through promoting PpIX‐elicited activation of sGC. Exposure of endothelium‐denuded bovine pulmonary arteries (BPA) in organoid culture to increasing concentrations of the heme precursor ALA caused a concentration‐dependent increase in the detection of PpIX fluorescence associated with decreased force generation to increasing concentrations of serotonin. The force‐depressing actions of 0.1 mM ALA were associated with increased cGMP‐associated VASP phosphorylation and increased sGC activity in arterial homogenates exposed to ALA. Increasing iron availability with 0.1 mM FeSO 4 inhibited the decrease in force and increase in sGC activity caused by ALA, associated with decreased PpIX and increased heme. Chelating endogenous iron with 0.1 mM deferoxamine increased the PpIX detection and force depressing activity of 10 μM ALA. The inhibition of sGC activation with the heme oxidant 10 μM ODQ attenuated the force depressing actions of a NO donor without altering the actions of ALA. Thus, control of endogenous formation of PpIX from ALA by the availability of iron is potentially a novel physiological mechanism of controlling vascular force generation through regulating the activity of sGC. (Supported by HL31069).