A A A

Pharmacology - Cardiovascular

Variations in the alpha2A-adrenergic receptor gene and their functional effects.

Kurnik D et al. 2006. Clin Pharmacol Ther. 79(3):173-85.

Abstract

The alpha2A-adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympathetic activity and hence cardiovascular responses such as heart rate and blood pressure. The objectives of this study were to systematically search for variants in the ADRA2A gene, to define the gene's haplotype structure, and to examine potential functional effects of these variants. We examined 5957 base pairs of contiguous sequence of ADRA2A (promoter, exonic, and 3'-flanking region) using polymerase chain reaction to amplify the genomic target, followed by bidirectional sequencing, in 135 healthy subjects (85 white and 50 black subjects). Haplotypes were inferred by use of an expectation-maximization algorithm. Primary (plasma norepinephrine concentration) and secondary (resting heart rate and blood pressure) phenotypes were compared among subjects grouped by individual polymorphisms and haplotypes. We identified 41 variants, including 24 novel variants. On the basis of 9 optimally selected markers, 11 haplotypes in 5 haplotype groups were inferred, representing approximately 99% of the cohort. Two uncommon variants in complete linkage disequilibrium (G>C at -1903 and C>G at -1607, identified in 3 black subjects) were associated with significantly increased plasma norepinephrine concentrations (376.7 +/- 6.1 pg/mL versus 218.4 +/- 95.0 pg/mL, P = .011). There was no other significant association between genetic variants or any of the haplotypes with phenotypes. We describe novel variants and the haplotype structure of the ADRA2A gene. Common genetic ADRA2A variants are not important determinants of baseline cardiovascular measures (plasma norepinephrine, heart rate, and blood pressure) in healthy volunteers.

Journal Link | PMID

Gene and cell-based therapies for heart disease.

Melo LG et al., 2004. FASEB J. 18(6):648-63

Abstract

Heart disease remains the prevalent cause of premature death and accounts for a significant proportion of all hospital admissions. Recent developments in understanding the molecular mechanisms of myocardial disease have led to the identification of new therapeutic targets, and the availability of vectors with enhanced myocardial tropism offers the opportunity for the design of gene therapies for both protection and rescue of the myocardium. Genetic therapies have been devised to treat complex diseases such as myocardial ischemia, heart failure, and inherited myopathies in various animal models. Some of these experimental therapies have made a successful transition to clinical trial and are being considered for use in human patients. The recent isolation of endothelial and cardiomyocyte precursor cells from adult bone marrow may permit the design of strategies for repair of the damaged heart. Cell-based therapies may have potential application in neovascularization and regeneration of ischemic and infarcted myocardium, in blood vessel reconstruction, and in bioengineering of artificial organs and prostheses. We expect that advances in the field will lead to the development of safer and more efficient vectors. The advent of genomic screening technology should allow the identification of novel therapeutic targets and facilitate the detection of disease-causing polymorphisms that may lead to the design of individualized gene and cell-based therapies.

Journal Link | PMID

 Click here to see many more resource citations on this topic.