Citations

The purpose of this study was to characterize changes in antioxidant and age-related gene expression in aorta and aortic valve with aging, and test the hypothesis that increased mitochondrial oxidative stress accelerates age-related endothelial and aortic valve dysfunction. Wild-type (MnSOD+/+) and manganese SOD heterozygous haploinsufficient (MnSOD+/−) mice were studied at 3 and 18 mo of age. In aorta from wild-type mice, antioxidant expression was preserved, although there were age-associated increases in Nox2 expression. Haploinsufficiency of MnSOD did not alter antioxidant expression in aorta, but increased expression of Nox2. When compared with that of aorta, age-associated reductions in antioxidant expression were larger in aortic valves from wild-type and MnSOD haploinsufficient mice, although Nox2 expression was unchanged. Similarly, sirtuin expression was relatively well-preserved in aorta from both genotypes, whereas expression of SIRT1, SIRT2, SIRT3, SIRT4, and SIRT6 were significantly reduced in the aortic valve. Expression of p16ink4a, a marker of cellular senescence, was profoundly increased in both aorta and aortic valve from MnSOD+/+ and MnSOD+/− mice. Functionally, we observed comparable age-associated reductions in endothelial function in aorta from both MnSOD+/+ and MnSOD+/− mice. Interestingly, inhibition of NAD(P)H oxidase with apocynin or gp91ds-tat improved endothelial function in MnSOD+/+ mice but significantly impaired endothelial function in MnSOD+/− mice at both ages. Aortic valve function was not impaired by aging or MnSOD haploinsufficiency. Changes in antioxidant and sirtuin gene expression with aging differ dramatically between aorta and aortic valve. Furthermore, although MnSOD does not result in overt cardiovascular dysfunction with aging, compensatory transcriptional responses to MnSOD deficiency appear to be tissue specific.

Studies in vitro and in vivo continue to identify complex-regulated mechanisms leading to overt fibrocalcific aortic valve disease (FCAVD). Assessment of the functional impact of those processes requires careful studies of models of FCAVD in vivo. Although the genetic basis for FCAVD is unknown for most patients with FCAVD, several disease-associated genes have been identified in humans and mice. Some gene products which regulate valve development in utero also protect against fibrocalcific disease during postnatal aging. Valve calcification can occur via processes that resemble bone formation. But valve calcification can also occur by nonosteogenic mechanisms, such as formation of calcific apoptotic nodules. Anticalcific interventions might preferentially target either osteogenic or nonosteogenic calcification. Although FCAVD and atherosclerosis share several risk factors and mechanisms, there are fundamental differences between arteries and the aortic valve, with respect to disease mechanisms and responses to therapeutic interventions. Both innate and acquired immunity are likely to contribute to FCAVD. Angiogenesis is a feature of inflammation, but may also contribute independently to progression of FCAVD, possibly by actions of pericytes that are associated with new blood vessels. Several therapeutic interventions seem to be effective in attenuating the development of FCAVD in mice. Therapies which are effective early in the course of FCAVD, however, are not necessarily effective in established disease.

Background and Purpose— Angiotensin II produces oxidative stress and endothelial dysfunction in cerebral arteries, and angiotensin II type I receptors may play a role in longevity and vascular aging. Angiotensin-converting enzyme type 2 (ACE2) converts angiotensin II to angiotensin (1–7) and thus, may protect against effects of angiotensin II. We hypothesized that ACE2 deficiency increases oxidative stress and endothelial dysfunction in cerebral arteries and examined the role of ACE2 in age-related cerebrovascular dysfunction. Methods— Endothelial function, expression of angiotensin system components, NADPH oxidase subunits, and proinflammatory cytokines were examined in cerebral arteries from adult (12 months old) and old (24 months old) ACE2 knockout (KO) and wild-type (WT) mice. The superoxide scavenger tempol was used to examine the role of oxidative stress on endothelial function. Results— Vasodilatation to acetylcholine was impaired in adult ACE2 KO (24±6% [mean±SE]) compared with WT mice (52±7%; P <0.05). In old mice, vasodilatation to acetylcholine was impaired in WT mice (29±6%) and severely impaired in ACE2 KO mice (7±5%). Tempol improved endothelial function in adult and old ACE2 KO and WT mice. Aging increased mRNA for tumor necrosis factor-α in WT mice, and significantly increased mRNA levels of NAPDH oxidase 2, p47 phox , and Regulator of calcineurin 1 in both ACE2 KO and WT mice. mRNA levels of angiotensin system components did not change during aging. Conclusions— ACE2 deficiency impaired endothelial function in cerebral arteries from adult mice and augmented endothelial dysfunction during aging. Oxidative stress plays a critical role in cerebrovascular dysfunction induced by ACE2 deficiency and aging.

Calcific aortic valve stenosis (CAVS) is a major health problem facing aging societies. The identification of osteoblast-like and osteoclast-like cells in human tissue has led to a major paradigm shift in the field. CAVS was thought to be a passive, degenerative process, whereas now the progression of calcification in CAVS is considered to be actively regulated. Mechanistic studies examining the contributions of true ectopic osteogenesis, nonosseous calcification, and ectopic osteoblast-like cells (that appear to function differently from skeletal osteoblasts) to valvular dysfunction have been facilitated by the development of mouse models of CAVS. Recent studies also suggest that valvular fibrosis, as well as calcification, may play an important role in restricting cusp movement, and CAVS may be more appropriately viewed as a fibrocalcific disease. High-resolution echocardiography and magnetic resonance imaging have emerged as useful tools for testing the efficacy of pharmacological and genetic interventions in vivo. Key studies in humans and animals are reviewed that have shaped current paradigms in the field of CAVS, and suggest promising future areas for research.