Ping Peipei, Baines Christopher P, Gu Yan, Prabhu Sumanth D, Zhang Jun, Tsai Linda L, Cardwell Ernest, Zong Nobel C, Vondriska Thomas M, Korge Paavo, Bhatnagar Aruni, Wang Guang-Wu
Department of Physiology, David Geffen School of Medicine at University of California, Los Angeles, USA.
Cardiovasc Toxicol. 2003;3(4):341-51. doi: 10.1385/ct:3:4:341.
Aldehydes are ubiquitous pollutants with well-indicated but ill-defined cardiovascular toxicity. To investigate the direct toxic effects of environmental aldehyde exposure on the myocardium, 8-wk-old male ICR (Institute of Cancer Research) strain mice were gavage fed trans-2-hexenal (0.1, 1, 10, or 50 mg/kg/wk) or corn oil (vehicle) for 4 wk, during which cardiac function, myocardial morphology, cardiomyocyte apoptosis, and the cytochrome cmediated caspase activation apoptotic pathway were determined. Quantification by enzyme-linked immunosorbent assay (ELISA) revealed that aldehyde- protein adducts increase in mouse hearts following hexenal treatment, whereas echocardiographic analysis displayed a significant impairment of basal left-ventricular contractile function. Both histological analysis and TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling) staining indicated condensed nuclei and a significant increase in cardiomyocyte apoptosis in these mice, but immunohistochemistry-based confocal microscope revealed no marked myofibril disarray. Release of cytochrome c from mitochondria into the cytosol, concomitant with activation of caspase-3 and -9, was also found in hexenal-treated groups. In addition, isolated cardiac mitochondria formed hexenal-protein adducts when treated with hexenal, providing indirect evidence that the cardiac mitochondrion is one of primary subcellular targets of aldehyde toxins. These findings suggest that trans-2-hexenal exposure results in direct cardiac toxicity through, at least in part, induction of mitochondrial cytochrome c release-mediated apoptosis in cardiomyocytes, indicating that the cardiac mitochondrion is one of principal subcellular targets of aldehyde toxins.
醛类是普遍存在的污染物，其心血管毒性已得到明确指示，但尚不明确。为了研究环境醛暴露对心肌的直接毒性作用，将8周龄雄性ICR（癌症研究所）品系小鼠用反式-2-己烯醛（0.1、1、10或50毫克/千克/周）或玉米油（赋形剂）灌胃4周，在此期间测定心脏功能、心肌形态、心肌细胞凋亡以及细胞色素c介导的半胱天冬酶激活凋亡途径。通过酶联免疫吸附测定（ELISA）进行定量分析显示，己烯醛处理后小鼠心脏中的醛蛋白加合物增加，而超声心动图分析显示左心室基础收缩功能显著受损。组织学分析和TUNEL（末端脱氧核苷酸转移酶介导的缺口末端标记）染色均表明这些小鼠的细胞核浓缩且心肌细胞凋亡显著增加，但基于免疫组织化学的共聚焦显微镜检查未发现明显的肌原纤维紊乱。在己烯醛处理组中还发现细胞色素c从线粒体释放到细胞质中，同时伴有半胱天冬酶-3和-9的激活。此外，分离的心脏线粒体在用己烯醛处理时会形成己烯醛蛋白加合物，这间接证明心脏线粒体是醛毒素的主要亚细胞靶点之一。这些发现表明，反式-2-己烯醛暴露至少部分通过诱导心肌细胞中线粒体细胞色素c释放介导的凋亡导致直接心脏毒性，这表明心脏线粒体是醛毒素的主要亚细胞靶点之一。
