Nitro-linoleic acid inhibits vascular smooth muscle cell proliferation via the Keap1/Nrf2 signaling pathway

Villacorta, Luis; Zhang, Jifeng; Garcia-Barrio, Minerva T.; Chen, Xi Lin; Freeman, Bruce Α.; Chen, Yuqing E.; Cui, Taixing

doi:10.1152/ajpheart.00261.2007

Cited by 129 publications

(105 citation statements)

References 85 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…Because cysteine residues are frequently functionally significant constituents of transcriptional regulatory proteins and enzymes, both adaptive and toxicological responses might occur on cysteine alkylation, and NO 2 -FA would be expected to influence numerous signaling pathways (12). Besides exhibiting potent anti-inflammatory effects by inhibition of NF-kB (11,14) and the signal transducer and activator of transcription (STAT) (15,16), activation of the Keap1/Nrf2 system (17), and induction of heat shock factor (18), NO 2 -FA also display beneficial metabolic effects by serving as partial agonists of peroxisome proliferatoractivated receptors (19,20). In a murine model of vascular injury, NO 2 -FA inhibited aortic vascular smooth muscle cell proliferation and migration via activation of heme oxygenase 1 expression and catalytic activity, thus significantly reducing neointima formation (21).…”

Section: Clinical Relevancementioning

confidence: 99%

Protective Effects of 10-nitro-oleic Acid in a Hypoxia-Induced Murine Model of Pulmonary Hypertension

Klinke

Möller²,

Pekarová

et al. 2014

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is characterized by adverse remodeling of pulmonary arteries. Although the origin of the disease and its underlying pathophysiology remain incompletely understood, inflammation has been identified as a central mediator of disease progression. Oxidative inflammatory conditions support the formation of electrophilic fatty acid nitroalkene derivatives, which exert potent anti-inflammatory effects. The current study investigated the role of 10-nitro-oleic acid (OA-NO 2 ) in modulating the pathophysiology of PAH in mice. Mice were kept for 28 days under normoxic or hypoxic conditions, and OA-NO 2 was infused subcutaneously. Right ventricular systolic pressure (RVPsys) was determined, and right ventricular and lung tissue was analyzed. The effect of OA-NO 2 on cultured pulmonary artery smooth muscle cells (PASMCs) and macrophages was also investigated. Changes in RVPsys revealed increased pulmonary hypertension in mice on hypoxia, which was significantly decreased by OA-NO 2 administration. Right ventricular hypertrophy and fibrosis were also attenuated by OA-NO 2 treatment. The infiltration of macrophages and the generation of reactive oxygen species were elevated in lung tissue of mice on hypoxia and were diminished by OA-NO 2 treatment. Moreover, OA-NO 2 decreased superoxide production of activated macrophages and PASMCs in vitro. Vascular structural remodeling was also limited by OA-NO 2 . In support of these findings, proliferation and activation of extracellular signal-regulated kinases 1/2 in cultured PASMCs was less pronounced on application of OA-NO 2 . Our results show that the oleic acid nitroalkene derivative OA-NO 2 attenuates hypoxia-induced pulmonary hypertension in mice. Thus, OA-NO 2 represents a potential therapeutic agent for the treatment of PAH.Keywords: pulmonary arterial hypertension; nitro-fatty acids; inflammation; hypoxia Clinical RelevancePulmonary hypertension is a severe disease whose pathophysiology is incompletely understood and for which therapeutic options are limited. The present study enforces the hypothesis that inflammatory and oxidative mechanisms play an important role in the development of pulmonary hypertension. Electrophilic nitro-fatty acids decreased hypoxia-induced pulmonary hypertension not only by antiinflammatory and antioxidant mechanisms but also by reducing smooth muscle cell proliferation via attenuation of extracellular signal-regulated kinases 1 and 2 activation. These findings suggest that nitro-fatty acids may serve as a new multimodal therapeutic approach in this disease.

show abstract

Section: Clinical Relevancementioning

confidence: 99%

Protective Effects of 10-nitro-oleic Acid in a Hypoxia-Induced Murine Model of Pulmonary Hypertension

Klinke

Möller²,

Pekarová

et al. 2014

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Reduction of inflammation and ox-LDL accumulation might thereby influence neointimal formation. The inhibitory effect of nitroalkene derivatives of linoleic acid (nitrolinoleate) on VSMC proliferation was also reported to act through activation of the Keap1=Nrf2 signaling pathway (114).…”

Section: Forkhead Box O (Foxo): Role In Antioxidant Defensementioning

confidence: 99%

Age-Related Changes in Redox Signaling and VSMC Function

Fukagawa

2010

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Epidemiological studies have shown that advancing age is associated with an increased prevalence of cardiovascular disease (CVD). Vascular smooth muscle cells (VSMC) comprise the major arterial cell population, and changes in VSMC behavior, function, and redox status with age contribute to alterations in vascular remodeling and cell signaling. Over two decades of work on aged animal models provide support for age-related changes in VSMC and=or arterial tissues. Enhanced production of reactive oxygen species (ROS) and insufficient removal by scavenging systems are hallmarks of vascular aging. VSMC proliferation and migration are core processes in vascular remodeling and influenced by growth factors and signaling networks. The intrinsic link between gene regulation and aging often relates directly to transcription factors and their regulatory actions. Modulation of growth factor signaling leads to up-or downregulation of transcription factors that control expression of genes associated with VSMC proliferation, inflammation, and ROS production. Four major signaling pathways related to the transcription factors, AP-1, NF-kB, FoxO, and Nrf2, will be reviewed. Knowledge of age-related changes in signaling pathways in VSMC that lead to alterations in cell behavior and function consistent with disease progression may help in efforts to attenuate age-related CVD, such as atherosclerosis. Antioxid. Redox Signal. 12, 641-655.

show abstract

“…The signaling pathway transducing the action of OA-NO 2 appears to be complex and remains to be defined particularly under pathophysiological condition in vivo. In vitro studies suggest that OA-NO 2 may signal through activation of peroxisome proliferator-activated receptors (PPARs) (3), S-alkylation of critical thiols of Keap-1, and subsequent activation of Nrf2 (4,16,27), covalent modification of the p65 subunit of NF-B, and suppression of its activity (9). A series of our previous studies demonstrates that OA-NO 2 is protective against kidney injury induced by ischemia-reperfusion and endotoxin-induced sepsis, and in obese Zucker rats (18, 29 -30).…”

mentioning

confidence: 99%