Acrolein generation stimulates hypercontraction in isolated human blood vessels
Introduction
Lipid peroxidation and inflammation can generate acrolein, a highly reactive α,β-unsaturated aldehyde. Oxidation of unsaturated fatty acids of lipoproteins and lipids forms alkoxyl and peroxyl radicals that decompose into several metastable carbonyl end products including acrolein (Grosch, 1987, Porter et al., 1995). Several disease states are associated with enhanced lipid peroxidation that lead to the accumulation of acrolein and acrolein–protein and acrolein–DNA adducts. Increased levels of acrolein have been measured in plasma of patients with renal failure (Sakata et al., 2003) and in Alzheimer's disease brain tissues (Lovell et al., 2001). Moreover, increased acrolein–protein adducts have been detected in vascular tissues of patients with diabetes (Daimon et al., 2003, Uesugi et al., 2004), Alzheimer's disease (Calingasan et al., 1999, Lovell et al., 2001), and atherosclerosis (Uchida, 1999, Uchida et al., 1998, Shao et al., 2005). Acrolein is also formed by myeloperoxidase-mediated oxidation of l-threonine, and thus activated neutrophils may contribute to vascular damage at sites of inflammation (Anderson et al., 1997). Other sources of tissue acrolein include glucose autoxidation-mediated oxidation of fatty acids (Medina-Navarro et al., 2004) and the oxidation of polyamines by amine oxidase (Gahl and Pitot, 1982), which is linked to polyamine-induced phase 2 enzymes (Kwak et al., 2003) and cytotoxicity (Sharmin et al., 2001).
Acrolein is also generated during metabolism of drugs and toxins. Metabolism of cyclophosphamide produces acrolein, which is implicated in the toxic action of the drug (i.e., hemorrhagic cystitis) (Kehrer and Biswal, 2000, Ren et al., 1999). Acrolein is formed in metabolism of allylamine (AA; an aliphatic amine used in the dye industry) by semicarbazide-sensitive amine oxidase (SSAO; EC 1.4.3.6; Boor and Nelson, 1982). Acute exposure of rats to AA in vivo causes SSAO-dependent subendocardial necrosis (Boor et al., 1979, Boor and Hysmith, 1987), and limited in vitro data indicate that this may result from coronary artery vasospasm (Conklin et al., 2001, Conklin and Boor, 1998). Thus, increased acrolein generation in the vascular wall from AA or other sources may well lead to vascular instability, altered vasoreactivity, and vasospasm.
Several diseases are associated with enhanced vascular inflammation, oxidative stress, and increased formation of acrolein and acrolein adducts in the blood vessel wall (Uchida et al., 1998). However, the effects of acrolein generation and accrual on vascular reactivity in human blood vessels are unknown. In a study of isolated rat coronary artery, we showed that direct acrolein exposure induces vasospasm-like effects and we validated the use of AA as an “acrolein generator” by showing that AA evokes SSAO-dependent effects similar to those of acrolein alone (Conklin et al., 2001, Conklin and Boor, 1998). Moreover, we confirmed the presence of a relatively high level of SSAO activity in human coronary arteries and coronary artery bypass graft (CABG) blood vessels that mediate methylamine-induced relaxation in CABG blood vessels (Conklin et al., 2001, Conklin et al., 2004). Thus, to simulate increased vascular production of acrolein associated with inflammation and lipid peroxidation and determine if acrolein generation promotes vasospasm in human blood vessels, we tested the direct effects of the acrolein generator AA. Herein we show that acrolein formation initiates hypercontraction via a calcium overload mechanism in human CABG blood vessels.
Section snippets
Human subjects
Adults (age years, mean ± SE, all, 62.8 ± 1.8; males, 59.9 ± 2.4, ≈ 77% of total; females, 71.9 ± 1.9; Table 1) undergoing CABG surgery at Luther Hospital/Midelfort Clinic (Eau Claire, WI) were the source of blood vessels. Unused sections of internal mammary artery (IMA), radial artery (RA), and saphenous vein (SV) were placed in lactated Ringers and refrigerated (4 °C) at the hospital. Vessels were retrieved between 4 and 16 h after surgery, cleaned of blood, staples, thread, and extraneous tissue, and
Acrolein generator AA induces hypercontraction in human blood vessels
AA pretreatment suppressed NE-induced tension in uncontracted vessels (data not shown), but in NE-precontracted CABG rings, 1 mM AA generally induced: (1) a triphasic response consisting of rapid and small contraction, sustained and robust relaxation, and spontaneous hypercontraction, (2) rapid inhibition of ACh- or SNP-induced relaxation, (3) sustained and elevated residual tension, and (4) a reduction in tension of HI K+-induced contraction (Fig. 1). Typically the onset of 1 mM AA-induced
Discussion
For many years, it has been proposed that reactive aldehydes as products of lipid peroxidation and inflammation contribute to progressive and deleterious changes in the hypertensive and atherosclerotic blood vessel wall (Shao et al., 2005, Uchida, 1999, Uchida et al., 1998, Anderson et al., 1997). In this study, we support this hypothesis in two specific ways: (1) real-time generation of acrolein in the blood vessel wall stimulates hypercontraction and (2) hypertension increases susceptibility
Acknowledgments
This work was supported by NIH Grant HL65416 (PJB), NIEHS AREA Grant 1R15 ES011141-01 (DJC), NIEHS 1P01 ES11860 (AB) NIEHS ES12062 (AB), NIH Grant GM48812 (LMS), and the University of Wisconsin-Eau Claire (UWEC) Office of Research and Sponsored Programs Student/Faculty Collaboration Grants, Summer Research Experience, University Research Creative Activity award (DJC), and the Ronald McNair Scholars Program at UWEC. We thank L. Eveland, M. Garney, D. Kranig, M. Phillips, E. Sackett, D.
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