4-hydroxy-2-nonenal and Hypertension--Pulmonary

Hypoxia-induced pulmonary hypertension (HPH) increases lipid peroxidation with generation of toxic aldehydes that are metabolized by detoxifying enzymes, including ALDH2 (aldehyde dehydrogenase 2). However, the role of lipid peroxidation and ALDH2 in HPH pathogenesis remain undefined. Approach and Results: To determine the role of lipid peroxidation and ALDH2 in HPH, C57BL/6 mice, ALDH2 transgenic mice, and ALDH2 knockout (ALDH2. Increased 4-hydroxynonenal level plays a critical role in the development of HPH. ALDH2 attenuates the development of HPH by regulating mitochondrial fission and smooth muscle cell proliferation suggesting ALDH2 as a potential new therapeutic target for pulmonary hypertension.

Topics: Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; Animals; Cell Proliferation; Cells, Cultured; Down-Regulation; Humans; Hypertension, Pulmonary; Hypoxia; Lipid Peroxidation; Lipoxygenases; Lung; Male; Malondialdehyde; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitochondrial Dynamics; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Pulmonary Artery; Reactive Oxygen Species; Up-Regulation

The cardioprotective benefits of aldehyde dehydrogenase 2 (ALDH2) are well established, although the regulatory role of ALDH2 in vascular remodeling in pulmonary arterial hypertension (PAH) is largely unknown. ALDH2 potently regulates the metabolism of aldehydes such as 4-hydroxynonenal (4-HNE), the endogenous product of lipid peroxidation. Thus, we hypothesized that ALDH2 ameliorates the proliferation and migration of human pulmonary artery smooth muscle cells (HPASMCs) by inhibiting 4-HNE accumulation and regulating downstream signaling pathways, thereby ameliorating pulmonary vascular remodeling. We found that low concentrations of 4-HNE (0.1 and 1μM) stimulated cell proliferation by enhancing cyclin D1 and c-Myc expression in primary HPASMCs. Low 4-HNE concentrations also enhanced cell migration by activating the nuclear factor kappa B (NF-κB) signaling pathway, thereby regulating matrix metalloprotein (MMP)-9 and MMP2 expression in vitro. In vivo, Alda-1, an ALDH2 agonist, significantly stimulated ALDH2 activity, reducing elevated 4-HNE and malondialdehyde levels and right ventricular systolic pressure in a monocrotaline-induced PAH animal model to the level of control animals. Our findings indicate that 4-HNE plays an important role in the abnormal proliferation and migration of HPASMCs, and that ALDH2 activation can attenuate 4-HNE-induced PASMC proliferation and migration, possibly by regulating NF-κB activation, in turn ameliorating vascular remodeling in PAH. This mechanism might reflect a new molecular target for treating PAH.

Topics: Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; Animals; Antihypertensive Agents; Benzamides; Benzodioxoles; Cell Line; Cell Movement; Cell Proliferation; Cyclin D1; Gene Expression Regulation; Hypertension, Pulmonary; Male; Malondialdehyde; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Monocrotaline; Myocytes, Smooth Muscle; NF-kappa B; Oxidative Stress; Proto-Oncogene Proteins c-myc; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Signal Transduction