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Am J Physiol Heart Circ Physiol 289: H202-H205, 2005. First published February 11, 2005; doi:10.1152/ajpheart.01287.2004
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Age-related changes of bradykinin B1 and B2 receptors in rat heart

Ekaterina Kintsurashvili, Arvi Duka, Ivana Ignjacev, Gregory Pattakos, Irene Gavras, and Haralambos Gavras

Hypertension and Atherosclerosis Section, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts

Submitted 21 December 2004 ; accepted in final form 4 February 2005


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
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Aging is a major risk factor for the development of vascular diseases, such as hypertension and atherosclerosis, that leads to end organ damage and especially heart failure. Bradykinin has been demonstrated to have a cardioprotective role by affecting metabolic processes and tissue perfusion under conditions of myocardial ischemia. Its actions are exerted via the bradykinin B1- and B2-type receptors (B1Rs and B2Rs), but the functional status of these receptors during the aging process is poorly understood. This study aims to investigate whether changes in B1R and B2R gene and protein expression in rat heart are associated with the age-related alterations of cardiac structure and function. Using real-time PCR, we found that B1R mRNA expression increased 2.9-fold in hearts of older rats (24 mo of age) compared with younger rats (3 mo of age), whereas B2R gene expression remained unchanged. Western blot analysis showed that expression of B2R at the protein level is approximately twofold higher in young rats compared with old rats, whereas the B1R protein is approximately twofold higher in old rats compared with young rats. The present results provide clear functional and molecular evidence that indicate age-related changes of bradykinin B1Rs and B2Rs in heart. Because the cardioprotective actions of bradykinin are physiologically mediated via the B2Rs, whereas the B1Rs become induced by tissue damage, these results suggest that age-related decreases in B2R protein levels may leave the heart vulnerable to ischemic damage, and increases in B1R expression and activity may represent a compensatory reaction in aging hearts.

myocardium; gene expression; receptor protein levels; aging; cardioprotection

AGING IS A MAJOR RISK FACTOR for the development of vascular diseases such as hypertension and atherosclerosis that lead to end organ damage, especially heart failure, the prevalence of which increases exponentially with age (22). Failure of the aging heart may also be related to structural and functional alterations in cardiac muscle cells. However, the molecular mechanisms underlying the age-related decline in cardiac function are largely unknown. Genes whose mRNA levels in cardiomyocytes change with aging may be causally related to pathological changes in heart or may reflect reactive responses to these changes.

Kinins are important peptide mediators of physiological and pathological functions of the cardiovascular system. A large body of literature has documented the cardioprotective properties of bradykinin (4, 10, 32). The effects of bradykinin are mediated by selective activation of two distinct G protein-coupled receptors, B1 and B2 receptors (B1R and B2R) (1, 3, 24). In the heart, these effects include coronary vasodilation, regulation of local blood flow, and increased vascular permeability (23, 26, 31). B2Rs are constitutively expressed and mediate the majority of the vascular and metabolic actions of bradykinin (2). In contrast, B1Rs are generally absent from normal tissues but become induced by a variety of pathological conditions including inflammation, the presence of cytokines, or tissue trauma (20, 25). Several studies have shown that, although bradykinin-mediated vasodilation is mostly B2R dependent, B1Rs can also contribute to this effect to a lesser extent (30), and this contribution varies in different species (21) and under different conditions (8). Bradykinin receptor stimulation leads to activation of the arachidonic acid cascade (3, 24) with stimulation of synthesis and release of autacoids such as prostaglandin I2 and nitric oxide (NO).

In a recent series of studies, we demonstrated that various experimental manipulations can increase the mRNA expression of these receptors in tissues of selected organs (5, 6, 17). In the absence of B2Rs, B1Rs assume the vasoactive but not the metabolic properties of B2Rs (5, 7). Many previous studies (11, 16, 27, 28, 33) have provided evidence for bradykinin receptors in the cardiovascular system such as in endothelial cells of aorta and pulmonary and coronary arteries, postcapillary venular vessels, and cerebral microvessels, but expression of bradykinin B1Rs and B2Rs in heart tissue is less explored. The present study was designed to investigate whether B1Rs and B2Rs are expressed in myocardium and whether they display age-related changes. This study provides information about the dynamics of B1R and B2R gene and protein expression with age, which could be useful in identifying candidate genes with potential roles as diagnostic and prognostic markers in age-associated cardiac diseases.


   MATERIALS AND METHODS
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Animals. Young (3 mo of age; 200–225 g body wt) and old (24 mo of age; 400–450 g body wt) male Brown Norway rats (n = 5/group) were purchased from the National Institute of Aging (National Institutes of Health; Bethesda, MD). The protocol was approved by the Boston University Institutional Animal Care and Use Committee.

Total RNA extraction and cDNA synthesis. Rats were euthanized with pentobarbital sodium, and the hearts were excised, washed with saline, weighed, and cleaned. Adipose tissues and great vessels were removed, and heart tissues were prepared for tissue receptor expression studies. Total RNA was isolated from hearts using TRIzol reagent according to the manufacturer’s instructions (Invitrogen; Carlsbad, CA); this was followed by DNase treatment and removal of contaminating DNA from the RNA preparation with DNA-free (Ambion; Austin, TX). The cDNA was generated from 2 µg of RNA by random hexamers using an RNA PCR kit (Perkin-Elmer; Branchburg, NJ) according to the manufacturer’s instructions.

Quantitative real-time PCR. Expression of B1Rs and B2Rs in the heart was examined by reverse transcription-polymerase chain reaction (RT-PCR) and analyzed with NIH Image J software as described previously (5–7, 17). Results were confirmed and analyzed more precisely using real-time PCR.

Real-time PCR reactions were performed and monitored with an ABI Prism 7900HT Sequence Detection System using a TaqMan protocol (Perkin-Elmer Applied Biosystems; Foster City, CA). Sequences for B1R and B2R were submitted to Applied Biosystems, and specific primers and probes were designed using Primer Express 2.1 software (Perkin-Elmer Applied Biosystems). Total gene specificity of the nucleotide sequences chosen for primers and probes was confirmed by results of BLAST searches (GenBank database sequences). The nucleotide sequences of the primers and probes were as follows: for B1R, the forward primer was 5'-CTGGCCCTTCGGAACTGA-3', the reverse primer was 5'-CAAACAGGTTGGCCTTGATGAC-3', and the probe was 5'-CCCGCTGACCACCC-3'; for B2R, the forward primer was 5'-ATCACCATCGCCAATAACTTCGA-3', the reverse primer was 5'-CACCACGCGGCACAG-3', and the probe was 5'-CACCTCTCCGAACAGC-3'.

Primers and probes for the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and 18S were purchased from Applied Biosystems.

In brief, the TaqMan assay requires both forward and reverse primers as well as a fluorogenic probe that anneals between the forward and reverse primer sites. The TaqMan probe has a fluorescent reporter dye at the 5' end and a quencher dye at the 3' end. During PCR cycling, the TaqMan probe is cleaved by 5'-3' nuclease activity of Taq polymerase, and reporter and quencher dyes become separated, which results in an increase in fluorescence. Details of the TaqMan assay have been described previously (13, 14, 19).

In our experiments, each well contained a 20-µl total reaction. For B1Rs and B2Rs, 9 µl of the RT product (from 400 and 200 ng of RNA, respectively) were used with 10 µl of TaqMan (2x) mix, 1 µl of primer and probe assay (20x) mix, 18 µM primers, and 5 µM probes. For 18S, 9.7 µl of the RT product (from 9.7 ng of RNA) were used with 10 µl of TaqMan (2x), 0.1 µl of 10 µM primers, and 0.1 µl of 40 µM probe. All reactions were run in triplicate and included negative controls. The first step was 2 min at 50°C, and the second step was denaturation for 15 s at 95°C; these were followed by annealing and extension at 60°C for 1 min.

The SDS 2.1 software generated a standard curve from 10-fold serial cDNA dilutions, and the threshold cycle was normalized for each standard curve. The range of slopes was between –3.40 and –3.55, where –3.33 corresponds to 100% efficiency of the PCR reaction. The copy numbers for all samples were normalized with the data obtained from 18S, which was used as a control.

Western blot analysis. Heart tissues from rats were prepared as described earlier, homogenized in buffer that contained (in mM) 50 Tris·HCl, 5 EDTA, and 150 NaCl with protease inhibitor cocktails, sonicated, and centrifuged at 51,500 g for 30 min at 4°C. The pellet was resuspended in the same buffer and homogenized again. Protein concentrations were determined by the Lowry method (Bio-Rad; Hercules, CA). Membrane protein (25 µg/lane) was loaded and separated on a 10% polyacrylamide gel by electrophoresis before transfer to nitrocellulose membranes. The membrane was blocked in 5% (wt/vol) nonfat dried milk. Nitrocellulose blots were washed in PBS-Tween 20 (0.05%) and then incubated for 2 h with a rat polyclonal antibody specific for rat B1R (1:200 dilution) or mouse B2R (1:1,000 dilution) antibodies followed by secondary antibody of horseradish peroxidase-conjugated anti-goat or anti-mouse IgG. B1R antibodies were purchased from Santa Cruz Biotechnology (Santa Cruz, CA), and B2R antibodies were from Transduction Laboratories (Lexington, KY). Antibody binding was visualized by the Enhanced Chemiluminescence Detection System (ECL). All blots were stripped with Western blot stripping buffer for 1 h (Pierce; Rockford, IL) and then washed for 1 h in Ponceau S solution (Sigma; St. Louis, MO).

Statistical analysis. Data are expressed as means ± SE. Statistical differences within groups were determined by one-way ANOVA. Statistical differences between young and old groups were compared by Student’s t-test. Values were considered to be significant when P < 0.05.


   RESULTS
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Quantitative RT-PCR. First, bradykinin B1R and B2R mRNA expression in the heart was determined using a quantitative RT-PCR. Representative RT-PCR results for B1R, B2R, and control 18S expression in rats of different ages are shown in Fig. 1. B1R expression was significantly higher in old rats compared with young rats, whereas B2R expression appeared to be similar for both age groups.



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  		Fig. 1. Representative RT-PCR for bradykinin B1- and B2-type receptor (B1R and B2R) gene expression in hearts. Lane 1, DNA size marker; lanes 2 and 3, B1R gene expression in young (Y) and old (O) rats; lanes 4 and 5, B2R gene expression in young and old rats; lanes 6 and 7, 18S controls for B1Rs and B2Rs.

 
Real-time PCR analysis of bradykinin B1R and B2R mRNA in hearts of young and old rats. For better assessment of gene expression changes, in the next experiments we used quantitative real-time PCR.

The choice of an internal control with consistent expression levels is critical in all quantitative analysis of gene expression. In our study, we found that the housekeeping gene GAPDH was decreased twofold in old rats compared with young rats. For this reason, 18S was selected as the internal control housekeeping gene. The normalized quantitative data of B1R and B2R mRNA expression in young and old rats are illustrated in Fig. 2, which shows that B1R mRNA expression was 2.9-fold higher (P < 0.05) in hearts of old rats (24 mo of age) compared with young rats (3 mo of age), whereas B2R gene expression was similar in the two groups (P = not significant).



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  		Fig. 2. Real-time PCR analysis of B1R mRNA in hearts of young (3 mo of age) and old (24 mo of age) rats.

 
Western blot analysis of bradykinin B1R and B2R proteins in hearts of young and old rats. Western blot analysis of rat heart protein extracts with bradykinin B1R antibodies revealed a strong signal in the 45-kDa range in old rats but almost half that amount in young rats. Densitometric analysis and normalization (with equal amounts of protein loading) of the immunoreactivity signal from protein extracts from hearts of young and old rats shows that the level of B1R protein was approximately two times higher in old rats vs. young rats. By contrast, the level of 42-kDa B2R protein was approximately two times higher in young rats compared with old rats (Fig. 3).



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  		Fig. 3. Western blot analysis of B1R (A) and B2R (B) proteins in hearts of young and old rats. Top: representative Western blot analysis. Mean densitometric data of protein expression level were analyzed using NIH Image J software (bottom). *P < 0.05, old vs. young rats; n = 5 rats/group.

 

   DISCUSSION
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Aging and age-related diseases are associated with altered patterns of gene expression that involve quantitative and qualitative changes in specific transcripts. A complete and simultaneous analysis of gene expression should therefore lead to important insights into the transcriptional mechanisms that underlie the aging process. Several genes have been identified as being involved in cellular protection and/or DNA repair after damage, inflammation, or stress. Aging may affect the expression or regulation of these genes and/or signal transduction and thereby increase the susceptibility of aged cardiomyocytes or vasculature to cardiovascular disease. For example, cardiac senescence was reported (15) to be associated with increased expression of ANG II type 1 and 2 receptors in different regions of myocardium, which might be the cause or the result of hemodynamic or humoral effects characteristic of advanced age. Alternatively, such changes may reflect compensatory responses to acute or chronic tissue damage.

In our present study, we describe differences in B1R and B2R gene and protein expression in hearts of rats at 3 and 24 mo of age. Using quantitative RT-PCR followed by real-time PCR for confirmation, we found that in hearts of young rats, B1R mRNA expression was minimal and barely detectable; in old rats, B1R gene expression was 2.9-fold higher than in young rats, whereas B2R gene expression was similar in both groups. By contrast, there was a twofold higher density of B2R protein in hearts of young compared with old rats, whereas the amount of B1R protein was approximately twofold higher in old than young rats. We assume that these differences reflect changes in receptor density within cells that are attributable to the aging process. However, it is also possible that they may reflect a different cellular composition in aging heart (e.g., increased preponderance of fibroblasts vs. cardiomyocytes). Because no information exists at this time regarding differential expression of these receptors in various types of cells, clarification of this point must await further research.

The discrepancy between differences in gene expression vs. differences in receptor protein amounts is intriguing. It suggests that for B1Rs, changes in expression at the genomic level resulted in changes at a downstream level, whereas for B2Rs, even in the absence of detectable changes in transcript, there may be changes at the protein level, which may be due to posttranscriptional regulation or protein turnover. This inability of an adequately expressed gene to generate the expected amount of protein could be attributable to some age-related deficiency. In turn, it also may be partly responsible for the compensatory upregulation of B1Rs; this idea is in keeping with previous findings indicating that in the absence of B2Rs, B1R genes become overexpressed and B1Rs take up the vasoregulatory functions that are normally mediated via B2Rs (5, 6).

It is tempting to speculate on the possible teleological significance of these differences, since there is very little information in the literature regarding the status of these receptors with relation to aging. As mentioned earlier, several studies in the past (4, 10, 11, 29, 32) have demonstrated that bradykinin, via B2R-mediated activation of the prostaglandin-NO cascade, acts to protect myocardium from ischemic and reperfusion-associated tissue damage. Furthermore, in the absence of B2Rs, B1Rs become upregulated and assume most of the vascular effects of B2Rs, because they also are capable of stimulating the prostaglandin-NO cascade (5, 6). However, the metabolic (insulin-sensitizing) effects of bradykinin were shown to be directly exerted through B2Rs without involvement of prostaglandins and NO, because they were not affected by cyclooxygenase and/or NO inhibitors (18). As a result, in the absence of B2Rs, the metabolic properties of bradykinin could not be restored by the upregulation of B1Rs (7, 12).

We can therefore speculate that the higher density of B2Rs in young animals would protect myocardium from ischemia-reperfusion-associated injury (23, 29, 32); furthermore, such injury occurring from mechanical or biochemical noxious stimuli (such as ANG II excess) can induce upregulation of B1Rs (6, 9, 17), which also contributes to cardioprotection via the prostaglandin-NO cascade. In old animals, the decline of B2R protein production with its metabolic consequences (diminished glucose utilization) would result in chronic tissue damage leading to compensatory upregulation of B1Rs, which may partially restore tissue perfusion but cannot restore the diminished insulin sensitivity that accompanies normal aging.

In summary, these studies demonstrate a striking difference in age-related changes in gene expression and protein generation of bradykinin receptors in myocardium; namely, B1R gene expression is minimal in young hearts, its protein generation is very low, and both increase commensurately in aging heart. By contrast, the B2R gene is equally expressed in young and old hearts, but the amount of receptor protein generated in old cardiomyocytes is approximately twofold lower. The data suggest that partial loss of the cardioprotective function of B2Rs with age may lead to a compensatory induction of B1R gene expression.


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This work was supported in part by National Heart, Lung, and Blood Institute Grants R01 HL-58807 and R01 HL-65311.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. Gavras, Hypertension and Atherosclerosis Section, Boston Univ. School of Medicine, 715 Albany St., Boston, MA 02118 (E-mail: hgavras{at}bu.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 DISCUSSION
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