The Pickering Lecture British Hypertension Society, 10th September 2002

Abstract

An elevation in angiotensin II (Ang II) levels is a common occurrence in a diverse number of cardiovascular diseases including hypertension, hypercholesterolaemia, atherosclerotic coronary artery disease, left ventricular hypertrophy (LVH), heart failure and diabetes. An important effect of Ang II is activation of the NAD(P)H oxidase, a major source of reactive oxygen species (ROS) production by vascular cells. This increase in cellular ROS contributes to the pathogenesis of vascular disease by altering endothelial cell function, enhancing smooth muscle cell growth and proliferation, stimulating inflammatory proteins, including macrophage chemoattractant agents, growth factors and cytokines, and modulating matrix remodelling. Studies of genetically-altered mice have unequivocally shown that activation of the NAD(P)H oxidase by Ang II contributes to hypertension, LVH and atherosclerosis. Furthermore, increasing evidence suggest that the NAD(P)H oxidase contributes to human disease, suggesting that it is a potential target for future therapeutic intervention.

Endothelial dihydrofolate reductase: Critical for nitric oxide bioavailability and role in angiotensin II uncoupling of endothelial nitric oxide synthase

“…Elevated angiotensin II levels have been observed in patients with atherosclerotic risk factors, including hypertension, diabetes, and renal dysfunction (2,5). Interestingly, angiotensin II stimulation (100 nmol͞liter for 24 h) of endothelial cells decreased DHFR expression by Ͼ50%, as reflected by representative Western blot and grouped data (Fig.…”

“…In hypertension-or diabetes-related atherosclerosis, angiotensin II is a major pathological player (5). Many of the untoward effects of angiotensin II have been attributed to its ability to stimulate ROS production from vascular NAD(P)H oxidases (1, 2).…”

“…Indeed, scavenging ROS restored endothelial function in animal models of hypertension and atherosclerosis (3). Antioxidant trials however produced mixed results in patients regarding disease prevention or regression, possibly because of incomplete understanding of antioxidant chemistry in vivo, inappropriate criteria for patient recruitment (4,5), or nonspecific nature of most antioxidants. The latter is an important issue to consider because it has remained unclear whether one particular ROS is dominantly important in pathological signaling (1).…”

Alpinate Oxyphyllae Fructus (Alpinia Oxyphylla Miq) Extracts Inhibit Angiotensin-II Induced Cardiac Apoptosis in H9c2 Cardiomyoblast Cells

“…Angiotensin II (Ang II) plays an important role in cardiovascular diseases such as hypertension, atherosclerosis, left ventricular hypertrophy (LVH), and heart failure. [4][5][6][7][8][9][10] Most studies indicate that Ang II induces cardiovascular hypertrophy, cardiac apoptosis, mitochondrial dysfunction, and cardiac remodeling through Ang II type 1 receptor (AT1R) activation, 4,7,11,12) but an opposing theory posits that this occurs via AT2R. [13][14][15][16][17] Although the functions of these two major Ang II receptors are ambiguous, the harm Ang II does cardiomyocytes is certain.…”

Advanced Glycation: Implications in Tissue Damage and Disease

“…Both mitochondrial and cytoslic sources of ROS have been shown to be mediated by AGEs. NAD(P)H oxidise consists of 5 subunits, the membranous p22phox and gp91phox (nox-1 and nox-4 homologues), the cytosolic subunits p47phox and p67phox and the regulatory G-protein [76]. The cytosolic subunits can assemble with the membranous subunits to form a functioning oxidase.…”