Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction, whether or not they have heart failure. We assessed the role of an angiotensin-converting-enzyme inhibitor, ramipril, in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure.A total of 9297 high-risk patients (55 years of age or older) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were randomly assigned to receive ramipril (10 mg once per day orally) or matching placebo for a mean of five years. The primary outcome was a composite of myocardial infarction, stroke, or death from cardiovascular causes. The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper.A total of 651 patients who were assigned to receive ramipril (14.0 percent) reached the primary end point, as compared with 826 patients who were assigned to receive placebo (17.8 percent) (relative risk, 0.78; 95 percent confidence interval, 0.70 to 0.86; P<0.001). Treatment with ramipril reduced the rates of death from cardiovascular causes (6.1 percent, as compared with 8.1 percent in the placebo group; relative risk, 0.74; P<0.001), myocardial infarction (9.9 percent vs. 12.3 percent; relative risk, 0.80; P<0.001), stroke (3.4 percent vs. 4.9 percent; relative risk, 0.68; P<0.001), death from any cause (10.4 percent vs. 12.2 percent; relative risk, 0.84; P=0.005), revascularization procedures (16.3 percent vs. 18.8 percent; relative risk, 0.85; P<0.001), cardiac arrest (0.8 percent vs. 1.3 percent; relative risk, 0.62; P=0.02), [corrected] heart failure (9.1 percent vs. 11.6 percent; relative risk, 0.77; P<0.001), and complications related to diabetes (6.4 percent vs. 7.6 percent; relative risk, 0.84; P=0.03).Ramipril significantly reduces the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure.

Effects of an angiotensin-converting -enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients

I. Introduction II. Molecular Aspects A. PPAR isotypes: identity, genomic organization and chromosomal localization B. DNA binding properties C. PPAR ligand-binding properties D. Alternative pathways for PPAR activation E. PPAR-mediated transactivation properties III. Physiological Aspects A. Differential expression of PPAR mRNAs B. PPAR target genes and functions in fatty acid metabolism C. PPARs and control of inflammatory responses D. PPARs and atherosclerosis E. PPARs and the development of the fetal epidermal permeability barrier F. PPARs, carcinogenesis, and control of the cell cycle IV. Conclusions

Peroxisome proliferator-activated receptors: nuclear control of metabolism.

▪ Abstract The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARγ, PPARα, and PPARδ, encoded by different genes. PPARs are ligand-regulated transcription factors that control gene expression by binding to specific response elements (PPREs) within promoters. PPARs bind as heterodimers with a retinoid X receptor and, upon binding agonist, interact with cofactors such that the rate of transcription initiation is increased. The PPARs play a critical physiological role as lipid sensors and regulators of lipid metabolism. Fatty acids and eicosanoids have been identified as natural ligands for the PPARs. More potent synthetic PPAR ligands, including the fibrates and thiazolidinediones, have proven effective in the treatment of dyslipidemia and diabetes. Use of such ligands has allowed researchers to unveil many potential roles for the PPARs in pathological states including atherosclerosis, inflammation, cancer, infertility, and demyelination. Here, we presen...

The Mechanisms of Action of PPARs

The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.

https://pharmrev.aspetjournals.org/content/pharmrev/52/3/415.full.pdf

International Union of Pharmacology. XXIII. The Angiotensin II Receptors

The PPARs: from orphan receptors to drug discovery.

The renin-angiotensin system has long been recognized as an important regulator of systemic blood pressure and renal electrolyte homeostasis, and local renin-angiotensin systems have also been implicated in pathological changes of organ structure and function by modulation of gene expression, growth, fibrosis, and inflammatory response. Recently, substantial data have been accumulated in support of the notion that adipose tissue, besides other endocrine functions, also hosts a local renin-angiotensin system. In the first part of this review, we describe the components of the adipose tissue renin-angiotensin system in human and rodent animal models with respect to regulation of angiotensinogen expression and secretion, formation of angiotensin peptides, and the existence of angiotensin II receptors. In the second part, we describe the role of the adipose tissue renin-angiotensin system in the process of adipogenic differentiation and in the regulation of body weight. We also detail the differential regulation of the adipose tissue renin-angiotensin system in obesity and hypertension and thereby also speculate on its possible role in the development of obesity-associated hypertension. Although some findings on the adipose tissue renin-angiotensin system appear to be confusing, its involvement in the physiology and pathophysiology of adipose tissue has been confirmed by several functional studies. Nevertheless, future studies with more carefully described phenotypes are necessary to conclude whether obesity (by stimulation of adipogenic differentiation) and hypertension are associated with changes of renin-angiotensin system activity in adipose tissue. If so, the physiological relevance of this system in animal models and humans may warrant further interest.

Physiology and Pathophysiology of the Adipose Tissue Renin-Angiotensin System

Objective The renin-angiotensin system plays a central role in blood pressure regulation, both by affecting renal function and by modulating vascular tone and structure. Recent studies in rodents demonstrated the existence of several components of this system in adipose tissue. The activity of the renin-angiotensin system appears to be regulated by food intake, suggesting that it may be involved in obesity-associated hypertension. Few data are available on the presence of renin-angiotensin system components in human adipose tissue. Materials and methods In order to explore the expression of renin-angiotensin system genes in human adipose tissue and adipocytes, total RNA was isolated from whole adipose tissue (subcutaneous and omental) or cultured adipocytes (mammary) and subjected to reversetranscriptase polymerase chain reaction with primers specific for human angiotensinogen, renin, renin-binding protein, angiotensin converting enzyme, chymase and type 1 and type 2 angiotensin receptors. Results Angiotensinogen, angiotensin converting enzyme and type 1 angiotensin receptor genes were widely expressed, both in human adipose tissue and in cultured human adipocytes. Furthermore, we found expression of the chymase and renin-binding protein genes in these samples. Conclusions Our findings suggest the presence of a local renin-angiotensin system in human adipose tissue, with adipocytes being an important part of this system, and prompt speculation that this local renin-angiotensin system may be involved in obesity-related disorders, including hypertension and the metabolic syndrome.

Co-expression of renin-angiotensin system genes in human adipose tissue.

Pro12ala missense mutation of the peroxisome proliferator activated receptor gamma and diabetes mellitus

Background. The angiotensinogen gene has been linked to the development of essential hypertension, and a M235T variant of this gene, associated with increased plasma levels of angiotensinogen, is more common in hypertensives than in normotensive controls in various populations. The present study was conducted to examine whether the M235T variant of the angiotensinogen gene may be a risk factor for the development of hypertension in patients undergoing renal transplantation. Methods. DNA for genetic analysis was prospectively collected from 269 consecutive patients undergoing kidney transplantation between 1988 and 1993 and their corresponding donors. Presence of hypertension and graft survival was analysed by blinded review of all case records over a follow-up period up to 30 months. Angiotensinogen genotype was determined by a mutagenically separated allele-specific polymerase-chain-reaction technique. Results. While post-transplant hypertension was present in 78% of all patients. no relationship was found between either donor or recipient genotype and the presence or severity of post-transplant hypertension. Furthermore, there was no relationship between angiotensinogen genotype and graft survival during the course of the study. Conclusions. These findings do not support the hypothesis that the M235T variant of the angiotensinogen gene is a risk factor for the development of post-transplant hypertension.

/pdf/angiotensinogen-m235t-genotype-and-post-transplant-3hg4aprhzn.pdf

Angiotensinogen-M235T genotype and post-transplant hypertension

https://www.future-science.com/doi/pdf/10.2144/98244bm03

Stefan Engeli

Papers

Physiology and Pathophysiology of the Adipose Tissue Renin-Angiotensin System

Co-expression of renin-angiotensin system genes in human adipose tissue.

Pro12ala missense mutation of the peroxisome proliferator activated receptor gamma and diabetes mellitus

Angiotensinogen-M235T genotype and post-transplant hypertension

Standardizing the counting of adipocytes in cell culture.