Acrolein but not its metabolite, 3-Hydroxypropylmercapturic acid (3HPMA), activates vascular transient receptor potential Ankyrin-1 (TRPA1): Physiological to toxicological implications.
Acrolein but not its metabolite, 3-Hydroxypropylmercapturic acid (3HPMA), activates vascular transient receptor potential Ankyrin-1 (TRPA1): Physiological to toxicological implications.
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丙烯醛而不是其代谢产物3-羟丙基巯基尿酸（3 HPMA）激活血管瞬时受体电位锚蛋白1（TRPA 1）：生理毒理学意义。
DOI：
10.1016/j.taap.2021.115647
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发表时间：
2021-09-01
影响因子：
3.8
通讯作者：
Conklin DJ
中科院分区：
文献类型：
--
作者：
Jin L;Lorkiewicz P;Xie Z;Bhatnagar A;Srivastava S;Conklin DJ
丙烯醛是一种亲电子α，β-不饱和醛，存在于食品和饮料中，是不完全燃烧的产物，因此在烟草烟雾和建筑火灾中达到高ppm水平。接触丙烯醛与心肺毒性和心血管疾病风险有关。本研究假设丙烯醛在离体小鼠血管（主动脉和上级肠系膜动脉，SMA）中的直接作用是瞬时受体电位锚蛋白1（TRPA 1）依赖性的。使用等长肌造影，离体主动脉和SMA暴露于增加水平的丙烯醛。丙烯醛以浓度依赖性（0.01-100 μM）方式抑制苯肾上腺素（PE）诱导的雄性和雌性小鼠主动脉和SMA收缩（约90%）。丙烯醛的主要代谢产物3-羟丙基巯基尿酸（3 HPMA）也能松弛PE预收缩的SMA。由于SMA对丙烯醛的敏感性比主动脉高20倍（SMA EC 50 0.8±0.2 μM;主动脉EC 50>29.4±4.4 μM），因此在SMA中研究了丙烯醛诱导的舒张机制。丙烯醛诱导的舒张作用可被以下物质显著抑制：1）机械损伤的内皮; 2）Nω-硝基-L-精氨酸甲酯盐酸盐（L-NAME）; 3）鸟苷酸环化酶（GC）抑制剂（ODQ）; 4）TRPA 1拮抗剂（A967079）。TRPA 1免疫荧光染色在内皮细胞上呈阳性。与其他已知的TRPA 1激动剂，包括异硫氰酸烯丙酯（AITC），肉桂醛，巴豆醛和甲醛相比，丙烯醛刺激更有效的TRPA 1依赖性舒张。高浓度[100 μM]的丙烯醛在收缩前SMA中诱导不依赖于TRPA 1的张力振荡（痉挛），但在主动脉中不诱导。总之，丙烯醛在低水平（生理学）时具有血管舒张作用，但在高水平（毒理学）时具有血管毒性。描绘SMA中丙烯醛诱导松弛机制的漫画。A）在SMA中，丙烯醛在低浓度下诱导血管舒张，在高浓度下伴随张力振荡（痉挛）损害收缩性。B）松弛机制（#1）始于内皮中瞬时受体电位锚蛋白1（TRPA 1）阳离子通道的敏感激活。通过用TRPA 1拮抗剂（A967079）预处理和通过使用TRPA 1缺失小鼠的SMA来阻断该步骤。当钙进入内皮细胞时，eNOS产生NO，并且该过程被NOS抑制剂（L-NAME）以及机械内皮破坏（空气灌注）特异性阻断。内皮NO扩散到血管平滑肌细胞（VSMC）中，激活可溶性鸟苷酸环化酶（sGC）以刺激cGMP形成，这一步骤被GC抑制剂（ODQ）预处理阻断。我们推断cGMP激活蛋白激酶G -一种已知的VSMC K+通道开放激活剂，导致超极化、电压门控Ca++通道关闭和血管舒张。内皮细胞在丙烯醛诱导的舒张中具有很强的作用，其部分由TRPA 1和NO介导，但可能涉及另一种内皮衍生因子（EDRF/EDHF; #1）。同样，我们推断第二种（但灵敏度低得多）非内皮依赖性松弛途径（#2）也存在，因为丙烯醛松弛SMA（和主动脉），即使在存在抑制剂和机械内皮破坏的情况下。该途径的机制可能涉及VSMC Ca++通道的打开/关闭，因为相对高浓度的丙烯醛诱导张力振荡（痉挛）。张力振荡的潜在机制仍有待确定，但这可能是重要的丙烯醛诱导的血管病变（血管痉挛）。
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 20x 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) nonendothelium 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).
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影响因子：
3.8
作者：
Conklin, D. J.;Bhatnagar, A.;Boor, P. J.
通讯作者：
Boor, P. J.
影响因子：
2.5
作者：
Anand, U.;Otto, W. R.;Anand, P.
通讯作者：
Anand, P.
谷胱甘肽S-转移酶P可预防小鼠环磷酰胺诱导的心脏毒性。
影响因子：
3.8
作者：
Conklin, Daniel J.;Haberzettl, Petra;Jagatheesan, Ganapathy;Baba, Shahid;Merchant, Michael L.;Prough, Russell A.;Williams, Jessica D.;Prabhu, Sumanth D.;Bhatnagar, Aruni
通讯作者：
Bhatnagar, Aruni
DOI：
10.1152/physiol.00026.2008
发表时间：
2008-12
期刊：
Physiology (Bethesda, Md.)
影响因子：
--
作者：
Bessac BF;Jordt SE
通讯作者：
Jordt SE
DOI：
10.1152/ajpheart.00106.2018
发表时间：
2019-04-01
影响因子：
4.8
作者：
Conklin, Daniel J.;Guo, Yiru;Bhatnagar, Aruni
通讯作者：
Bhatnagar, Aruni