Background— Arterial stiffness is an independent determinant of cardiovascular risk, and arterial stiffening is the predominant abnormality in systolic hypertension. Elastin is the main elastic component of the arterial wall and can be degraded by a number of enzymes, including matrix metalloproteinase-9 (MMP-9) and MMP-2. We hypothesized that elastase activity would be related to arterial stiffness and tested this using isolated systolic hypertension (ISH) as a model of stiffening and separately in a large cohort of healthy individuals. Methods and Results— A total of 116 subjects with ISH and 114 matched controls, as well as 447 individuals free from cardiovascular disease were studied. Aortic and brachial pulse wave velocity (PWV) and augmentation index were determined. Blood pressure, lipids, C-reactive protein, MMP-9, MMP-2, serum elastase activity (SEA), and tissue-specific inhibitor 2 of metalloproteinases were measured. Aortic and brachial PWV, MMP-9, MMP-2, and SEA levels were increased in ISH subjects compared with controls ( P =0.001). MMP-9 levels correlated linearly and significantly with aortic ( r =0.45; P =0.001) and brachial PWV ( r =0.22; P =0.002), even after adjustments for confounding variables. In the younger, healthy subjects, MMP-9 and SEA were also independently associated with aortic PWV. Conclusions— Aortic stiffness is related to MMP-9 levels and SEA, not only in ISH, but also in younger, apparently healthy individuals. This suggests that elastases including MMP-9 may be involved in the process of arterial stiffening and development of ISH.

Background— Arterial stiffness is an important determinant of cardiovascular risk. Elastin is the main elastic component of the arterial wall and can be degraded by a number of enzymes including serine proteases and matrix metalloproteinases (MMPs). Serum MMP-9 levels correlate with arterial stiffness and predict cardiovascular risk. Polymorphisms in the MMP-9 gene are also associated with large artery function in subjects with coronary artery disease. Therefore, we investigated the influence of known MMP-9 (−1562C>T, R279Q) polymorphisms on arterial stiffness in a large cohort of healthy individuals (n=865). Methods and Results— Aortic pulse wave velocity (PWV) and augmentation index were assessed. Supine blood pressure, biochemical markers, MMP-9 levels, and serum elastase activity (SEA) were also determined. Genomic DNA was extracted and genotyping performed. Aortic PWV, serum MMP-9, and SEA were higher in carriers of the rare alleles for the −1562C>T and R279Q polymorphisms. These polymorphisms were also associated with aortic PWV after correction for other confounding factors. Stepwise regression models with known or likely determinants of arterial stiffness revealed that ≈60% of the variability in aortic PWV was attributable to age, mean arterial pressure, and genetic variants ( P <0.001). Conclusions— We have demonstrated for the first time that aortic stiffness and elastase activity are influenced by MMP-9 gene polymorphisms. This suggests that the genetic variation in this protein may be involved in the process of large artery stiffening.

Stiffening of the aorta is an important independent risk factor for myocardial infarction and stroke. Yet its genetics is complex and little is known about its molecular drivers. We have identified for the first time, tagSNPs in the genes for extracellular matrix proteins, aggrecan and fibulin-1, that modulate stiffness in young healthy adults. We confirmed SNP associations with ex vivo stiffness measurements and expression studies in human donor aortic tissues. Both aggrecan and fibulin-1 were found in the aortic wall, but with marked differences in the distribution and glycosylation of aggrecan reflecting loss of chondroitin-sulphate binding domains. These differences were age-dependent but the striking finding was the acceleration of this process in stiff versus elastic young aortas. These findings suggest that aggrecan and fibulin-1 have critical roles in determining the biomechanics of the aorta and their modification with age could underpin age-related aortic stiffening.

Arterial stiffness may be an early marker for vascular changes associated with hypertension in young adults. We investigated whether arterial stiffness measured as augmentation index and pulse wave velocity is increased in offspring of families with essential hypertension, and whether stiffness is related to various biochemical markers. Two groups of subjects were investigated: offspring of families with essential hypertension (mean age 39 years), and normotensive control subjects (mean age 43 years). Pulse wave analysis was used to estimate augmentation index (AIx, %). Brachial pulse wave velocity (PWV, m/sec), blood pressure, homocysteine, and creatinine were determined by standard methods. The offspring had significantly higher systolic, diastolic, mean arterial pressures, as well as higher homocysteine, creatinine, and glucose levels compared with normotensive control subjects. Augmentation index, but not brachial pulse wave velocity, was significantly higher in offspring (P = .010) compared with control subjects. This group difference in AIx was evident in a regression model that corrected for the known cardiovascular risk factors (P = .027). In all subjects, homocysteine associated positively with brachial PWV (r = 0.15, P < .01) and negatively with AIx (r = -0.12, P < .05). AIx also associated inversely with creatinine in the whole group (r = -0.34; P < .001) and in offspring (r = -0.38; P < .001) only. A significant positive correlation was also observed between homocysteine and creatinine in all subjects (r = 0.30; P < .001), in men (r = 0.23; P < .05) and women (r = 0.26; P < .005), respectively. These data suggests that large artery abnormalities may be present early in subjects likely to develop hypertension.

Cardiovascular disease is the leading cause of death worldwide and premature arterial stiffening is a key contributor to this risk. A large body of evidence now points to arterial stiffness as an independent predictor of cardiovascular events. Stiffness can be assessed by a number of indices and is itself affected by factors including mean arterial pressure, vascular smooth muscle tone and structural elements in the vessel wall, such as elastin and collagen. In addition, aging, hypertension, diabetes and hypercholesterolaemia all exacerbate the stiffening process. Stiffness is highly heritable but, despite a clear genetic basis, the precise molecular pathways regulating stiffness are poorly understood. The present review provides an overview of the current literature and examines the evidence that links genetic factors to arterial wall properties. Although the findings support stiffness as a complex genetic trait, the precise nature of the genes contributing to this are still largely unknown. There are a number of candidate genes and many of these could potentially affect the structure and function of the arterial wall. Indeed, it is likely that genes involving signalling pathways and control of the vessel wall matrix will be as important as those involved in the renin–angiotensin system, adrenergic and other vasoactive systems. Identifying the genes involved is important, since it may suggest new biomarkers as well as provide novel drug targets to reduce arterial stiffness. Current pharmacological intervention is simply to reduce blood pressure, but there are emerging therapies; for example, targeted at breaking collagen cross-links or preventing their formation, which are promising new strategies to reduce arterial stiffness and its associated cardiovascular risk.

Vascular aging is characterized by vessel stiffening, with increased deposition of extracellular matrix (ECM) proteins including collagens. Oxidative DNA damage occurs in vascular aging, but how it regulates ECM proteins and vascular stiffening is unknown. We sought to determine the relationship between oxidative DNA damage and ECM regulatory proteins in vascular aging. We examined oxidative DNA damage, the major base excision repair (BER) enzyme 8-Oxoguanine DNA Glycosylase (Ogg1) and its regulators, multiple physiological markers of aging, and ECM proteomics in mice from 22-72w. Vascular aging was associated with increased oxidative DNA damage, and decreased expression of Ogg1, its active acetylated form, its acetylation regulatory proteins P300 and CBP, and the transcription factor Foxo3a. Vascular stiffness was examined in vivo in control, Ogg1^-/-, or mice with vascular smooth muscle cell-specific expression of Ogg1⁺ (Ogg1) or an inactive mutation (Ogg1^KR). Ogg1^-/- and Ogg1^KR mice showed reduced arterial compliance and distensibility, and increased stiffness and pulse pressure, whereas Ogg1 expression normalised all parameters to 72w. ECM proteomics identified major changes in collagens with aging, and downregulation of the ECM regulatory proteins Protein 6-lysyl oxidase (LOX) and WNT1-inducible-signaling pathway protein 2 (WISP2). Ogg1 overexpression upregulated LOX and WISP2 both in vitro and in vivo, and downregulated Transforming growth factor β1 (TGFb1) and Collagen 4α1 in vivo compared with Ogg1^KR. Foxo3a activation induced Lox, while Wnt3 induction of Wisp2 also upregulated LOX and Foxo3a, and downregulated TGFβ1 and fibronectin 1. In humans, 8-oxo-G increased with vascular stiffness, while active OGG1 reduced with both age and stiffness. Vascular aging is associated with oxidative DNA damage, downregulation of major BER proteins, and changes in multiple ECM structural and regulatory proteins. Ogg1 protects against vascular aging, associated with changes in ECM regulatory proteins including LOX and WISP2. Schematic illustrating changes in Ogg1, Foxo3a, Wisp2, Lox, Tgfb and ECM proteins in vascular aging and after Ogg1 overexpression Aging is associated with downregulation of p300 and reduced expression and acetylation of OGG1, resulting in persistently increased oxidative DNA damage. Persistent oxidative DNA damage results in p53 activation and reduced Wisp2, resulting in reduced Foxo3a and Lox and increased Tgfb1, leading to multiple features promoting vascular stiffness. Rescue of Ogg1 expression reduces oxidative DNA damage and prevents many of these features occurring.