Cyclic Strain and Hypertension Increase Osteopontin Expression in the Aorta.

Hypertension has a direct impact on vascular hypertrophy and is a known risk factor for the development of atherosclerosis. Osteopontin (OPN) has emerged as an important protein mediator of inflammation and remodeling of large arteries. However, its role and mechanism of regulation in the setting of hypertension is still unknown. Our objectives for this study were therefore to investigate the role of OPN in hypertension-induced vascular remodeling and inflammation. OPN Knockout (KO) and wild type (WT) mice were made hypertensive with angiotensin II (Ang II) infusion for seven days. We observed that OPN KO aortas were protected against Ang II-induced medial hypertrophy and inflammation, despite comparable increases in systolic blood pressure (SBP) in both groups. OPN expression was increased in WT aortas from hypertensive mice (induced by either Ang II or norepinephrine). OPN expression was increased in aortic smooth muscle cells (SMCs) subjected to cyclic mechanical strain suggesting that mechanical deformation of the aortic wall is responsible in part for the increased OPN expression induced by hypertension. Finally, we utilized hypertensive transgenic smooth muscle cell-specific catalase overexpressing (TgSMC-Cat) mice to determine the role of H2O2 in mediating hypertension-induced increases in OPN expression. We also found that the hypertension-induced increase in OPN expression was inhibited in transgenic smooth muscle cell-specific catalase overexpressing (TgSMC-Cat) mice, suggesting that H2O2, plays a vital role in mediating the hypertension-induced increase in OPN expression. Taken together, these results define a potentially important role for OPN in the pathophysiology of hypertension.

HERPUD1 protects against oxidative stress-induced apoptosis through downregulation of the inositol 1,4,5-trisphosphate receptor.

Homocysteine-inducible, endoplasmic reticulum (ER) stress-inducible, ubiquitin-like domain member 1 (HERPUD1), an ER resident protein, is upregulated in response to ER stress and Ca(2+) homeostasis deregulation. HERPUD1 exerts cytoprotective effects in various models, but its role during oxidative insult remains unknown. The aim of this study was to investigate whether HERPUD1 contributes to cytoprotection in response to redox stress and participates in mediating stress-dependent signaling pathways. Our data showed that HERPUD1 protein levels increased in HeLa cells treated for 30 min with H2O2 or angiotensin II and in aortic tissue isolated from mice treated with angiotensin II for 3 weeks. Cell death was higher in HERPUD1 knockdown (sh-HERPUD1) HeLa cells treated with H2O2 in comparison with control (sh-Luc) HeLa cells. This effect was abolished by the intracellular Ca(2+) chelating agent BAPTA-AM or the inositol 1,4,5-trisphosphate receptor (ITPR) antagonist xestospongin B, suggesting that the response to H2O2 was dependent on intracellular Ca(2+) stores and the ITPR. Ca(2+) kinetics showed that sh-HERPUD1 HeLa cells exhibited greater and more sustained cytosolic and mitochondrial Ca(2+) increases than sh-Luc HeLa cells. This higher sensitivity of sh-HERPUD1 HeLa cells to H2O2 was prevented with the mitochondrial permeability transition pore inhibitor cyclosporine A. We concluded that the HERPUD1-mediated cytoprotective effect against oxidative stress depends on the ITPR and Ca(2+) transfer from the ER to mitochondria.