Biomedical subjects

Yasser Saad

Publications and source records attributed to Yasser Saad.

6 recordsLinked to original sources

PubMed2007

Fine-mapping and comprehensive transcript analysis reveals nonsynonymous variants within a novel 1.17 Mb blood pressure QTL region on rat chromosome 10.

The presence of blood pressure (BP) quantitative trait loci (QTL) on rat chromosome 10 has been clearly demonstrated by linkage analysis and substitution mapping. Using congenic strains containing the LEW rat chromosomal segments on the Dahl salt-sensitive (S) rat background, further iterations of congenic substrains were constructed and characterized to fine-map a chromosome 10 region (QTL1) linked to blood pressure. Comparison of seven congenic substrains refined QTL1 to a 1.17 Mb segment flanked by D10Mco88 and D10Mco89, which are located at 71,513,116 and 72,684,774 bp, respectively. The newly defined QTL1, containing 18 genes, is captured in its entirety within a single congenic substrain. A thorough transcript analysis revealed that 3 of these 18 genes, Ccl5, Ddx52, and RGD1559577, had nonsynonymous allelic variations between the S rat and the LEW rat. None of the detected transcripts within the newly defined QTL1 are implicated directly in BP control in humans or model organisms. Therefore, the present work defines a novel blood pressure QTL with three potential quantitative trait nucleotides.

Animals↗

PubMed2006

Angiotensinergic stimulation of vascular endothelium in mice causes hypotension, bradycardia, and attenuated angiotensin response.

It is not clear whether endothelial cell (EC) activation by the hormone angiotensin II (Ang II) modulates contraction of vascular smooth muscle cells (VSMCs) in the vasculature and whether impairment of this regulation in vivo contributes to hypertension. Delineation of the actions of Ang II through the type 1 receptor (AT1R) on ECs in the blood vessels has been a challenging problem because of the predominance of the AT1R functions in VSMCs that lie underneath the endothelium. We have obviated this limitation by generating transgenic (TG) mice engineered to target expression of the constitutively active N111G mutant AT1R only in ECs. In these TG mice, the enhanced angiotensinergic signal in ECs without infusion of Ang II resulted in hypotension and bradycardia. The pressor response to acute infusion of Ang II was significantly reduced. Increased expression of endothelial nitric oxide synthase and production of hypotensive mediators, nitric oxide and cyclic guanosine monophosphate, cause these phenotypes. Hypotension and bradycardia observed in the TG mice could be rescued by treatment with an AT1R-selective antagonist. Our results imply that the Ang II action by means of EC-AT1R is antagonistic to vasoconstriction in general, and it may moderate the magnitude of functional response to Ang II in VSMCs. This control mechanism in vivo most likely is a determinant of altered hemodynamic regulation involved in endothelial dysfunction in hypertensive cardiovascular disease.

Angiotensins↗

PubMed2005

Characterization and functional significance of myotrophin: a gene with multiple transcripts.

The underlying mechanism for the development of cardiac hypertrophy that advances to heart failure is not known. Many factors have been implied to play a role in this process. Among others, we have isolated and identified myotrophin, a factor that stimulates myocytes growth, from spontaneously hypertensive rat (SHR) heart and patients with dilated cardiomyopathy. The gene encoding myotrophin has been cloned and expressed in E. coli. Recently, myotrophin gene has been mapped and shown to be a novel gene localized in human chromosome 7q-33. To define the characteristics of each transcript and its pathophysiological significance, we examined transcripts of myotrophin in SHR heart during progression of hypertrophy. Northern blot analysis of myotrophin mRNA showed multiple transcripts. We isolated and characterized various myotrophin cDNA clones corresponding to the multiple transcripts by 5' "stretch plus" rat heart cDNA library screening. Sequence analysis of these cDNA clones indicates that each clone has a unique 5' UTR and multiple 3' UTR with varying lengths, repeated ATTTA motifs and many polyadenylation signals. In vitro transcripts generated from all these myotrophin-specific cDNA clones translate in vitro to a 12-kD protein. Among pathophysiological significance, we determined mRNA expression in 9 days old, 3 weeks old and 31 weeks old and observed a linear increased during the progression of hypertrophy. In WKY, this mRNA level remained the same throughout the growth and development of hypertrophy. Our data strongly suggest that myotrophin appears to be a candidate gene for cardiac hypertrophy and heart failure.

Amino Acid Sequence↗

PubMed2004

"Network leaning" as a mechanism of insurmountable antagonism of the angiotensin II type 1 receptor by non-peptide antagonists.

A mechanistic understanding of the insurmountable antagonism of the angiotensin II type 1 (AT(1)) receptor could be fundamental in the quest for discovery and improvement of drugs. Candesartan and EXP3174 are competitive, reversible insurmountable antagonists of the AT(1) receptor. They contain di-acidic substitutions, whereas the surmountable antagonist, losartan, contains only one acidic group. We tested the hypothesis that these two classes of ligands interact with the AT(1) receptor through similar but not identical bonds and that the differences in the acid-base group contacts are critical for insurmountable antagonism. By pharmacological characterization of site-directed AT(1) receptor mutants expressed in COS1 cells we show that specific interactions with Gln(257) in transmembrane 6 distinguishes insurmountable antagonists and that abolishing these interactions transforms insurmountable to surmountable antagonism. In the Q257A mutant, the dissociation rate of [(3)H]candesartan is 2.8-fold more than the rate observed with wild type, and the association rate was reduced 4-fold lower than the wild type. The pattern of antagonism of angiotensin II concentration-response in the Q257A mutant pretreated with EXP3174 and candesartan is surmountable. We propose that leaning ability of insurmountable antagonists on Gln(257) in the wild-type receptor is the basis of an antagonist-mediated conformational transition, which is responsible for both slow dissociation and inhibition of maximal IP response.

Amino Acid Sequence↗

PubMed2004

Cardiac angiotensin II receptors as predictors of transplant coronary artery disease following heart transplantation.

AIMS: We tested the hypothesis that cardiac angiotensin II (Ang II) receptor gene transcription may predict the development of transplant coronary artery disease (TCAD) following heart transplantation. METHODS AND RESULTS: We examined the gene transcripts of Ang II type 1 (AT1R) and type 2 receptors (AT2R) in endomyocardial biopsy specimens from 50 heart transplant recipients. The progression of TCAD was measured as change in maximal intimal thickness (CMIT) and change in plaque volume (CPV) by intravascular ultrasound (IVUS) examinations from baseline to one year after transplantation. The development of transplant vasculopathy was defined as a CMIT of > or = 0.3 mm over one year. The level of AT(1)R mRNA was associated with that of AT2R in transplanted hearts (regression coefficient=1.77, 95% CI 0.85-2.89, p<0.0001). AT1R and AT2R gene transcripts were univariate predictors of CMIT (AT1R: regression coefficient 0.10, 95% CI 0.06-0.14, p<0.0001; AT2R: regression coefficient 0.28, 95% CI 0.17-0.40, p<0.0001 ) or CPV (AT1R: regression coefficient 0.41, 95% CI 0.17-0.65, p<0.0001 ; AT2R: regression coefficient 1.25, 95% CI 0.49-2.01, p=0.002 ). By one year, 21 (46%) transplant recipients showed evidence of transplant vasculopathy and the rest did not. The vasculopathic group demonstrated a higher level of expression of cardiac AT1R than the non-vasculopathic group (3.7+/-2.9 vs 1.6+/-1.7 folds; p=0.006). The level of AT(1)R mRNA in transplanted heart was identified as a discriminator that predicted the development of transplant vasculopathy with a sensitivity of 75% and specificity of 83%. CONCLUSIONS: Cardiac Ang II receptor gene transcripts are associated with the progression of TCAD following heart transplantation. Only AT1R gene transcripts predicted the development of transplant vasculopathy in this preliminary study. These findings potentially support a role of Ang II receptors in the progression of TCAD following cardiac transplantation.

Acute Disease↗

PubMed2003

Activation of G-protein-coupled receptors: a common molecular mechanism.

G-protein-coupled receptors (GPCRs) are a large family of proteins that contain a seven transmembrane helical structural motif. They mediate responses to several ligands by binding and activating intracellular heterotrimeric G proteins. Since the cloning of the first GPCR, insights gained from structure-function studies, genetics and drug development have contributed to uncovering a common mechanism that explains the activation of diverse GPCRs by their cognate agonists. This mechanism takes into consideration the conservation of the structure-function relationship in the basic seven transmembrane structural motif, and the dynamic changes in receptor conformation that are associated with activation. Combining models derived from the X-ray structure of rhodopsin with structure-function data allows a deeper understanding of the activation mechanism of GPCRs.

Binding Sites↗