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CLINICAL STUDY

Down-regulation of cardioprotective bradykinin type-2 receptors in the left ventricle of patients with end-stage heart failure

Antti Kuoppala, MD^*, Naotaka Shiota, MD, PhD^*, Jorma O. Kokkonen, MD, PhD^*, Inka Liesmaa, MD^*, Karam Kostner, MD, PhD, Mikko Mäyränpää, MD^*, Petri T. Kovanen, MD, PhD^* and Ken A. Lindstedt, PhD^*,*

^* Wihuri Research Institute, Helsinki, Finland
Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland
Division of Cardiology, Allegemeines Krankenhaus, Vienna, Austria

Manuscript received September 20, 2001; revised manuscript received March 25, 2002, accepted April 5, 2002.

^* Reprint requests and correspondence: Dr. Ken A. Lindstedt, Wihuri Research Institute, Kalliolinnantie 4, FIN-00140 Helsinki, Finland.
ken.lindstedt{at}wri.fi

OBJECTIVES: We sought to study the expression of bradykinin type-2 receptors (BK-2Rs) in patients with heart failure (HF).

BACKGROUND: Recent work in experimental animals has suggested that bradykinin (BK) exerts cardioprotective effects through specific BK-2Rs. However, nothing is known about the regulation of BK-2R expression in the pathogenesis of human HF.

METHODS: Human heart tissue was obtained from excised hearts of patients undergoing cardiac transplantation (n = 13) and from normal hearts (n = 6) unsuitable for donation. The patients had HF due to idiopathic dilated cardiomyopathy (IDC) (n = 7) or coronary heart disease (CHD) (n = 6). Tissue samples from the left ventricles were analyzed by competitive reverse-transcriptase-polymerase chain reaction and Western blotting for the expression of BK-2R messenger ribonucleic acid (mRNA) and protein.

RESULTS: In both the IDC and CHD hearts, the level of BK-2R mRNA expression was found to be significantly lower (30% and 38% of control values, respectively) than that in normal hearts. Correspondingly, the BK-2R protein level was significantly reduced in both the IDC and CHD hearts (45% and 62% of control values, respectively) and apparently involved all myocardial cell types. The down-regulation of BK-2R expression in failing hearts did not correlate with decreased cellularity or with the expression pattern of other members of the G-protein–coupled receptor superfamily. However, BK-2R down-regulation in the failing hearts was associated with a decrease in endothelial nitric oxide synthase in both IDC (53% of control value) and CHD (43% of control value) hearts.

CONCLUSIONS: These results are the first to suggest that a loss of BK-2Rs is involved in the pathogenesis of human HF.

Abbreviations and Acronyms   ACE   angiotensin-converting enzyme   AT-1R   angiotensin II type 1 receptor   AT-2R   angiotensin II type 2 receptor   BK   bradykinin   BK-2R   bradykinin type-2 receptor   CHD   coronary heart disease   DNA   deoxyribonucleic acid   eNOS   endothelial nitric oxide synthase   GAPDH   glyceraldehyde-3-phosphate dehydrogenase   HCAEC   human coronary artery endothelial cell   HF   heart failure   IDC   idiopathic dilated cardiomyopathy   LVH   left ventricular hypertrophy   PCR   polymerase chain reaction   RNA   ribonucleic acid   RT-PCR   reverse-transcriptase polymerase chain reaction

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