Abstract
Accumulating work in experimental animals suggests that bradykinin (BK) exerts cardioprotective effects via bradykinin type-2 receptors (BK-2Rs). In human end-stage heart failure, BK-2Rs are significantly downregulated by mechanisms that have remained elusive. Heart tissues from idiopathic dilated cardiomyopathy (IDC; n = 7), coronary heart disease (CHD; n = 6), and normal patients (n = 6) were analyzed by RT-PCR, SSCP, and Western blotting. In normal and IDC hearts, BK-2R expression increased with age, with a lower relative increase in IDC hearts. BK-2R mRNA and protein levels showed a positive linear correlation, suggesting transcriptional regulation. Two known BK-2R promoter polymorphisms, −58T/C and −9/+9, were found to be present in the study population. The allelic frequencies for the C-allele in −58T/C were 0.58 in normal and CHD hearts and 0.81 in IDC hearts. Furthermore, the allelic frequencies for the −9 and +9 alleles were 0.42 and 0.58 in normal hearts and 0.64 and 0.36 in IDC hearts, respectively. All analyzed CHD hearts were homozygous for the −9 allele. Thus, the expression of cardioprotective BK-2Rs in human hearts is increased with age in normal and IDC hearts and may be regulated on the transcriptional level. Moreover, comparison of normal subjects and patients with failing hearts revealed different allelic frequencies in each of two known BK-2R gene polymorphisms.
Highlights
Accumulating data indicate that bradykinin (BK) exerts cardioprotective effects, which include both protection of the myocardium from ischemia-reperfusion injuries [1,2,3,4] and prevention of left ventricular hypertrophy (LVH) and heart failure [5,6,7]
Recent data by Duka et al have indicated that both BK-1Rs and bradykinin type-2 receptors (BK-2Rs) contribute to the maintenance of normal blood pressure in Wistar rats, but that one receptor can compensate for inhibition of the other, and that a chronic inhibition of both receptors resulted in significant upregulation of related vasoactive systems [17]
The relative increase in BK-2R mRNA expression, that is the slope of the regression curve, was significantly lower in the idiopathic dilated cardiomyopathy (IDC) hearts than in the normal hearts
Summary
Accumulating data indicate that bradykinin (BK) exerts cardioprotective effects, which include both protection of the myocardium from ischemia-reperfusion injuries [1,2,3,4] and prevention of left ventricular hypertrophy (LVH) and heart failure [5,6,7]. The cardioprotective effects are mainly mediated by the bradykinin type-2 receptor (BK-2R), a member of the G protein-coupled receptor superfamily, resulting in vasodilatation, that is release of nitric oxide by endothelial cells [4, 5, 8], together with both antiproliferative [6, 9] and antihypertrophic [7, 10] effects on fibroblasts and myocytes. The observed reduction in BK-2R expression associated with a decrease in endothelial nitric oxide synthase (eNOS) in the failing hearts and with an increase in the level of fibrosis in IDC hearts [11]. The +9 allele of a −9/+9 exon 1 polymorphism
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