Abstract 5323: Inhibition of NADPH Oxidase is Not Sufficient for Protection Against Age-associated Changes in Atherosclerosis, Arterial Phenotype and Cardiac Function
The incidence of cardiovascular diseases (CVD) increases with age. Increased inflammation and ROS levels were implicated in this process. To examine the interplay of aging, ROS and CVD, we performed vascular phenotyping of young (4 months) and aged (16 months) apoE−/− and apoE−/−/p47phox−/− mice fed a normal or Western diet. As we previously reported, young apoE−/−/p47phox−/− mice had significantly less atherosclerosis compared to apoE−/− mice. However, a significant increase in atherosclerosis was observed in aged apoE−/−/p47phox−/− compared to young apoE−/−/p47phox−/− mice, regardless of the diet. Significant decrease in aortic compliance was observed in aged apoE−/− and apoE−/−/p47phox−/− compared to the respective young mice regardless of the diet. Left ventricle (LV) ejection fraction was significantly decreased in the aged mice while LV end diastolic volume, LV mass and posterior wall thickness were significantly increased compared with young mice of the same genotype. Aortic sections from aged apoE−/− and apoE−/−/p47phox−/− mice showed increased collagen, decreased elastin content and focal calcification. Increased total and mitochondrial ROS production was also observed in aortic sections from aged apoE−/− and apoE−/−/p47phox−/− mice compared to those in young mice of the same genotype. Aortic vascular smooth muscle cells (VSMC) from aged wild-type and p47phox−/− mice had higher levels of total and mitochondrial ROS compared to VSMC from respective young mice. ROS levels were higher in aged p47phox−/− VSMC. Expression of Nox1 and Nox4 subunits was significantly increased in aged vs young wild-type VSMC while only a modest increase was observed in aged p47phox−/− animals as detected by RT-PCR and histochemistry. Expression of uncoupling protein 2 and PPARγ coactivator 1 was significantly increased in aged wild-type but decreased in aged p47phox−/− VSMC compared to the respective young VSMC indicating higher mitochondrial membrane potential and increased mitochondrial dysfunction in p47phox−/− cells. Together, these data suggest that suppression of NADPH oxidase activity is not sufficient for protection from age-associated changes in VSMC and cardiovasculature and from atherosclerosis in the presence of hypercholesterolemia.