Arterial stiffness.

Measurements of biomechanical properties of arteries have become an important surrogate outcome used in epidemiological and interventional cardiovascular research. Structural and functional differences of vessels in the arterial tree result in a dampening of pulsatility and smoothing of blood flow as it progresses to capillary level. A loss of arterial elastic properties results a range of linked pathophysiological changes within the circulation including increased pulse pressure, left ventricular hypertrophy, subendocardial ischaemia, vessel endothelial dysfunction and cardiac fibrosis. With increased arterial stiffness, the microvasculature of brain and kidneys are exposed to wider pressure fluctuations and may lead to increased risk of stroke and renal failure. Stiffening of the aorta, as measured by the gold-standard technique of aortic Pulse Wave Velocity (aPWV), is independently associated with adverse cardiovascular outcomes across many different patient groups and in the general population. Therefore, use of aPWV has been proposed for early detection of vascular damage and individual cardiovascular risk evaluation and it seems certain that measurement of arterial stiffness will become increasingly important in future clinical care. In this review we will consider some of the pathophysiological processes that result from arterial stiffening, how it is measured and factors that may drive it as well as potential avenues for therapy. In the face of an ageing population where mortality from atheromatous cardiovascular disease is falling, pathology associated with arterial stiffening will assume ever greater importance. Therefore, understanding these concepts for all clinicians involved in care of patients with cardiovascular disease will become vital.

Protein kinase D1 modulates aldosterone-induced ENaC activity in a renal cortical collecting duct cell line.

Aldosterone treatment of M1-CCD cells stimulated an increase in epithelial Na(+) channel (ENaC) alpha-subunit expression that was mainly localized to the apical membrane. PKD1-suppressed cells constitutively expressed ENaCalpha at low abundance, with no increase after aldosterone treatment. In the PKD1-suppressed cells, ENaCalpha was mainly localized proximal to the basolateral surface of the epithelium both before and after aldosterone treatment. Apical membrane insertion of ENaCbeta in response to aldosterone treatment was also sensitive to PKD1 suppression as was the aldosterone-induced rise in the amiloride-sensitive, trans-epithelial current (I(TE)). The interaction of the mineralocorticoid receptor (MR) with specific elements in the promoters of aldosterone responsive genes is stabilized by ligand interaction and phosphorylation. PKD1 suppression inhibited aldosterone-induced SGK-1 expression. The nuclear localization of MR was also blocked by PKD1 suppression and MEK antagonism implicating both these kinases in MR nuclear stabilization. PKD1 thus modulates aldosterone-induced ENaC activity through the modulation of sub-cellular trafficking and the stabilization of MR nuclear localization.

Confirmation that the renin gene distal enhancer polymorphism REN-5312C/T is associated with increased blood pressure.

BACKGROUND: Studies of knockout and transgenic mice have demonstrated key roles for genes encoding components of the renin angiotensin system in blood pressure regulation. However, whether polymorphisms in these genes contribute to the cause of essential hypertension in humans is still a matter of debate. METHODS AND RESULTS: We performed an experiment with dense tagging single-nucleotide polymorphism coverage of 4 genes encoding proteins that control the overall activity of the cascade, namely renin, angiotensinogen, angiotensin-converting enzyme, and angiotensin-converting enzyme 2, in 2 Irish populations. Both clinic and 24-hour ambulatory blood pressure measurements were available from population I (n=387), whereas just clinic blood pressure was measured in population II (n=1024). Of the 23 polymorphisms genotyped, only a single renin gene polymorphism, REN-5312C/T, showed consistent statistically significant associations with elevated diastolic pressures. Carriage of one REN-5312T allele was associated with the following age- and sex-adjusted increments in diastolic pressures (mean [95% CI]): population I, clinic, 1.5 mm Hg (0.3 to 2.8); daytime, 1.4 mm Hg (0.4 to 2.4); night-time, 1.3 mm Hg (0.4 to 2.3), and population II, clinic, 1.1 mm Hg (0.1 to 2.1). Haplotypic analyses and multivariate stepwise regression analyses were in concordance with individual single-nucleotide polymorphism analyses. CONCLUSIONS: The REN-5312T allele had been shown previously to result in increased in vitro expression of the renin gene. We have now shown, in 2 independent populations, that carriage of a REN-5312T allele is associated with elevated diastolic blood pressure. These data provide evidence that renin is an important susceptibility gene for arterial hypertension in whites.