The renin-angiotensin system, composed of enzymatic and signal-transduction cascades, plays a key role in the regulation of arterial blood pressure and in the development of certain forms of experimental and human hypertension. The products of this system, angiotensin peptides, exert a wide range of physiologically important effects on many tissues, including those of the cardiovascular system, through their actions on angiotensin receptors. Molecular genetic and transgenic studies have begun to implicate some of the genes encoding components of the renin-angiotensin system in the development of cardiovascular diseases. Recently, we succeeded in generating mice homozygous for a targeted disruption of the angiotensinogen gene (the only known precursor of angiotensins), resulting in the complete loss of angiotensin signals in vivo. Here, we review new developments related to the functional analysis of the renin-angiotensin system, in particular, by focusing on transgenic approaches including gene targeting.
"Coupled with the presence of chymosin (Foltmann 1992) and pepsins (Ryle & Porter 1959) in the stomach to aid digestion and the presence of cathepsin D in the lysosome to aid protein degradation (Erickson & Blobel 1979), it was generally believed that aspartic proteases fell within a group classified as 'non-specific' degradation enzymes. However, this is not the case for all aspartic proteases, as evident from the specific processing roles that aspartic proteases play; for example, memapsin 2 (BACE; Vassar et al. 1999, Lin et al. 2000) and g-secretase (Wolfe et al. 1999) in the pathogenesis of Alzheimer's disease, or from the role of renin in the generation of angiotensin I (Fukamizu & Murakami 1995) and its function in the regulation of blood pressure. The yapsins (Cawley & Loh 2011) may also represent an exception to this classification. "
[Show abstract][Hide abstract] ABSTRACT: Yapsin 1 is an aspartic protease from Saccharomyces cerevisiae and belongs to a class of aspartic proteases that demonstrate specificity for basic amino acids. It is capable of processing prohormone substrates at specific basic residue cleavage sites, similar to that of the prohormone convertases, to generate bioactive peptide hormones. An antibody raised against yapsin 1 was previously shown to immunostain endocrine cells of rat pituitary and brain as well as lysates from bovine pituitary secretory granules demonstrating the existence of yapsin 1-like aspartic proteases in mammalian endocrine tissues, potentially involved in peptide hormone production. Here, we show the specific staining of yapsin 1 immunoreactivity in the α-cells of human pancreatic islets. No staining was observed in the β- or δ-cells, indicating a specificity of the staining for glucagon-producing and not insulin- or somatostatin-producing cells. Purified yapsin 1 was also shown to process proglucagon into glucagon in vitro, demonstrating that the prototypical enzyme of this subclass of enzymes can correctly process proglucagon to glucagon. These findings suggest the existence of a yapsin 1-like enzyme exclusively in the α-cells of the islets of Langerhans in humans, which may play a role in the production of glucagon in that tissue.
Journal of Endocrinology 06/2011; 210(2):181-7. DOI:10.1530/JOE-11-0121 · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent genetic studies indicate that several molecular variants discovered in angiotensinogen (AG), the precursor of vasoactive octapeptide angiotensin II, could potentially be responsible for inherited predisposition to human blood pressure variation. We have previously shown that a ubiquitously expressed nuclear factor, AGCF1, bound to AGCE1 (AG core promoter element 1 including the core nucleotides, CTCGTG, CTC-type) located between the TATA box and transcription initiation site (positions -25 to -1) is an authentic regulator of human AG transcription. In the present study, we showed that AGCF1 has biologically and immunologically similar properties to those of a helix-loop-helix nuclear factor USF1 and examined the effects of two other naturally occurring molecular variants (ATCGTG, ATC-type and ATTGTG, ATT-type) found in the AGCE1 position on the human AG transcriptional activity. Competitive gel-shift and transfection experiments demonstrated that the transcriptional activity for the CTC- and ATC-type promoters was 2.5 times higher than that for the ATT-type through the alteration of AGCF1-binding affinity. These results suggest the possible involvement of USF1 as a component in AGCF1 formation and the potential importance of AGCE1 variation in blood pressure regulation through human AG expression.
[Show abstract][Hide abstract] ABSTRACT: Proteinases (also called proteases or peptidases) are classified on the basis of their mechanisms of peptide-bond cleavage
and are referred to in this regard by the nucleophile used to attack the carbonyl carbon of the scissile bond. Since proteins
are one of the fundamental building blocks of biological systems, proteinases are essential regulators of biological activity.
For example, they are directly involved in such diverse physiologic processes as fertility and reproduction, cellular proliferation,
tissue remodeling, wound healing, clotting, clot dissolution, digestion, and protein turnover. Similarly, an increased understanding
of the causative role proteinases play in a number of disease processes (such as cancer invasion and metastasis, the inflammatory
response, antigen processing and presentation, degenerative diseases, and cardiovascular/pulmonary disorders) has led to an
increased effort to exploit the potential of proteinase inhibition as a therapeutic alternative for a variety of diseases.
Previous chapters in this book have focused on the potential for novel therapies based on the inhibition of exogenous, pathogen-derived
proteinases for important human diseases ranging from human immunodeficiency-virus (HIV) infection to periodontal disease.
The following chapters are intended to give the reader a general understanding and appreciation of the potential that inhibition
of endogenous or host proteinases may have for the treatment of a variety of human disorders or conditions.
Proteases as Targets for Therapy, 12/1999: pages 207-219;
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