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Acrolein but not its metabolite, 3-Hydroxypropylmercapturic acid (3HPMA), activates vascular transient receptor potential Ankyrin-1 (TRPA1): Physiological to toxicological implications

Jin, L. ; Lorkiewicz, P. ; Xie, Z. ; Bhatnagar, A. ; Srivastava, S. ; Conklin, D.J.

Toxicology and applied pharmacology, 2021-09, Vol.426, p.115647-115647, Article 115647 [Periódico revisado por pares]

United States: Elsevier Inc

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  • Título:
    Acrolein but not its metabolite, 3-Hydroxypropylmercapturic acid (3HPMA), activates vascular transient receptor potential Ankyrin-1 (TRPA1): Physiological to toxicological implications
  • Autor: Jin, L. ; Lorkiewicz, P. ; Xie, Z. ; Bhatnagar, A. ; Srivastava, S. ; Conklin, D.J.
  • Assuntos: Acetylcysteine - analogs & derivatives ; Acetylcysteine - blood ; Acetylcysteine - pharmacology ; Acrolein - blood ; Acrolein - pharmacology ; Aldehydes ; Animals ; Aorta, Thoracic - drug effects ; Aorta, Thoracic - physiology ; Endothelium ; Female ; Glutathione S-Transferase pi - genetics ; Glutathione S-Transferase pi - physiology ; GTPase-Activating Proteins - genetics ; GTPase-Activating Proteins - physiology ; Male ; Mesenteric artery ; Mesenteric Artery, Superior - drug effects ; Mesenteric Artery, Superior - physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nitric oxide (NO) ; TRPA1 Cation Channel - genetics ; TRPA1 Cation Channel - physiology ; Vasospasm
  • É parte de: Toxicology and applied pharmacology, 2021-09, Vol.426, p.115647-115647, Article 115647
  • Notas: LJ and DC planned, conducted the experiments, generated, analyzed and interpreted data, and wrote the manuscript. PL, ZX, AB, and SS edited the manuscript. DC is the guarantor of this work. As such, he had full access to all data and takes responsibility for the integrity and accuracy of the data.
    Author contributions
  • Descrição: Acrolein, an electrophilic α,β-unsaturated aldehyde, is present in foods and beverages, and is a product of incomplete combustion, and thus, reaches high ppm levels in tobacco smoke and structural fires. Exposure to acrolein is linked with cardiopulmonary toxicity and cardiovascular disease risk. The hypothesis of this study is the direct effects of acrolein in isolated murine blood vessels (aorta and superior mesenteric artery, SMA) are transient receptor potential ankyrin-1 (TRPA1) dependent. Using isometric myography, isolated aorta and SMA were exposed to increasing levels of acrolein. Acrolein inhibited phenylephrine (PE)-induced contractions (approximately 90%) in aorta and SMA of male and female mice in a concentration-dependent (0.01–100 μM) manner. The major metabolite of acrolein, 3-hydroxypropylmercapturic acid (3HPMA), also relaxed PE-precontracted SMA. As the SMA was 20× more sensitive to acrolein than aorta (SMA EC50 0.8 ± 0.2 μM; aorta EC50 > 29.4 ± 4.4 μM), the mechanisms of acrolein-induced relaxation were studied in SMA. The potency of acrolein-induced relaxation was inhibited significantly by: 1) mechanically-impaired endothelium; 2) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME); 3) guanylyl cyclase (GC) inhibitor (ODQ); and, 4) a TRPA1 antagonist (A967079). TRPA1 positive immunofluorescence was present in the endothelium. Compared with other known TRPA1 agonists, including allyl isothiocyanate (AITC), cinnamaldehyde, crotonaldehyde, and formaldehyde, acrolein stimulated a more potent TRPA1-dependent relaxation. Acrolein, at high concentration [100 μM], induced tension oscillations (spasms) independent of TRPA1 in precontracted SMA but not in aorta. In conclusion, acrolein is vasorelaxant at low levels (physiological) yet vasotoxic at high levels (toxicological). Cartoon depicting the mechanisms of acrolein-induced relaxation in SMA. A) Acrolein induced vasorelaxation at low concentrations and impaired contractility with tension oscillations (spasms) at high concentrations in SMA. B) The mechanism of relaxation (#1) starts with sensitive activation of the Transient Receptor Potential Ankyrin 1 (TRPA1) cation channel in the endothelium. This step was blocked by pretreatment with a TRPA1 antagonist (A967079) and by using SMA of TRPA1-null mice. Upon calcium entry into endothelial cells, eNOS generates NO, and this process was blocked specifically by a NOS inhibitor (L-NAME) as well as by mechanical endothelial disruption (air perfusion). Endothelial NO diffuses into vascular smooth muscle cells (VSMC) activating soluble guanylyl cyclase (sGC) to stimulate cGMP formation, a step blocked by pretreatment with the GC inhibitor (ODQ). We infer that cGMP activated Protein Kinase G – a known activator of K+ channel opening in VSMC leading to hyperpolarization, closure of voltage-gated Ca++ channels, and vasorelaxation. There is a strong role of endothelial cells in acrolein-induced relaxation that is partly mediated by TRPA1 and NO but likely involves another endothelial-derived factor (EDRF/EDHF; #1). Likewise, we infer a second (yet far less sensitive) non-endothelium dependent pathway of relaxation (#2) also exists because acrolein relaxes SMA (and aorta) even in the presence of inhibitors and mechanical endothelium disruption. The mechanism of this pathway may involve opening/closing of VSMC Ca++ channels because acrolein at relatively high concentrations induces tension oscillations (spasms). The underlying mechanism of tension oscillations remains to be determined but this may be important in acrolein-induced vasculopathy (vasospasm). [Display omitted] •Acrolein induces a concentration-dependent relaxation in isolated SMA of male and female mice.•Acrolein activates TRPA1, eNOS and guanylyl cyclase to induce vasorelaxation in SMA.•Acrolein induces a more potent relaxation in SMA than other TRPA1 agonists or 3HPMA.•The TRPA1 antagonist, A967079, relaxes isolated SMA independent of TRPA1.
  • Editor: United States: Elsevier Inc
  • Idioma: Inglês
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