Mechanical Strain induced Osteopontin Expression in the Aorta (LB45)

Abstract

We have previously shown that elevated mechanical strain in disease states, such as hypertension, leads to vascular inflammation. However the underlying mechanisms modulating this process are still largely unknown. In this study, we used in‐vivo and in‐vitro approaches to determine if mechanical strain increases osteopontin (OPN), a pro‐inflammatory protein, in a hydrogen peroxide (H2O2) and NADPH oxidase dependent manner.Utilizing two mouse models of hypertension, induced by angiotensin‐II (AngII) or norepinephrine (NE) infusion, we found blood pressure was increased 1.5 and 1.3 fold, respectively. Aortic OPN mRNA was increased 7 and 2.5 fold (p<0.05) in the AngII and NE treated groups, respectively. OPN protein was also increased in both models. In AngII treated aortas of transgenic mice that overexpress catalase, a H2O2 scavenger, in vascular smooth muscle cells, we found a decrease in hypertension‐induced OPN mRNA expression compared to wild type littermate controls.In‐vitro studies using rat aortic smooth muscle cells (RASMs) that were cyclically strained showed a 3 fold (p<0.001) increase in OPN mRNA and 5 fold (p<0.001) increase in OPN protein. H2O2 levels were also increased 4 fold (p<0.05). RASMs strained in the presence of catalase exhibited blunted OPN protein compared to untreated, strained RASMs (72.6% decrease, p<0.05). Finally, RASMs strained in the presence of NADPH oxidase inhibitors, DPI and apocynin, showed a significant decrease in strain‐induced OPN protein compared to untreated, strained RASMs (77.6% decrease, p<0.01 and 43.8% decrease, p<0.05, respectively).These results suggest that mechanical strain, as experienced by the vascular wall under hypertensive conditions, leads to increases in osteopontin via an NADPH oxidase and H2O2‐dependent pathway.Grant Funding Source: American Heart Association, Predoctoral Fellowship