(Hypertension. 1998;31:39.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Bradykinin Blocks Angiotensin II–Induced Hypertrophy in the Presence of Endothelial Cells
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Abstract |
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Abstract—Angiotensin-converting enzyme inhibitors block left ventricular hypertrophy in vivo. A component of this effect has been attributed to tissue accumulation of bradykinin. Little is known regarding the effect of bradykinin on cardiomyocytes. The objectives of the present study were to define the effects of bradykinin on isolated ventricular cardiomyocytes (from adult and neonatal rat hearts) and to determine the extent to which bradykinin blocks hypertrophy in vitro. Bradykinin was found to be a hypertrophic agonist, as defined by increased protein synthesis and atrial natriuretic peptide secretion and expression. Bradykinin (10 µmol/L) increased [3H]phenylalanine incorporation by 23±3% in adult and by 36±10% in neonatal cardiomyocytes. Constitutive atrial natriuretic peptide secretion by neonatal myocytes was increased 357±103%. All effects of bradykinin were abolished by the B2-kinin receptor antagonist Hoe 140. These increases were similar in magnitude to those observed with phenylephrine (20 µmol/L) and angiotensin II (1 µmol/L). However, in cardiomyocytes cocultured with endothelial cells, bradykinin did not increase protein synthesis. Angiotensin II increased [3H]phenylalanine incorporation by 24±3% in adult cardiomyocytes in monoculture and by 22±2% in adult rat cardiomyocytes cocultured with endothelial cells. Bradykinin abolished this angiotensin II–induced hypertrophy in myocytes cultured with endothelial cells but not in myocytes studied in the absence of endothelial cells. In conclusion, bradykinin has a direct hypertrophic effect on ventricular myocytes. The presence of endothelial cells is required for the antihypertrophic effects of bradykinin. The results suggest that the increase in local concentration of bradykinin associated with angiotensin-converting enzyme inhibition is an important mechanism by which hypertrophy can be blocked. Manifestation of this mechanism appears to require bradykinin-stimulated release of paracrine factor(s) from endothelial cells, which are also able to block the hypertrophic effects of Ang II.
Key Words: angiotensin-converting enzyme inhibitors • atrial natriuretic peptide • protein synthesis • angiotensin II • bradykinin • phenylephrine
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Introduction |
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In vivo, the development of LVH is a compensatory response to increased cardiac work. LVH is associated with increases in cell size and protein synthesis of VCMs. Expression of embryonic gene products such as ANP is also increased.1 2 Hypertrophy can be induced in vitro by cell stretch, which is suppressed with angiotensin type 1 receptor antagonists.3 Ang II has therefore been implicated as a mediator of hypertrophy.4 5 This is supported by direct induction of hypertrophy by Ang II5 6 7 and the presence of a local cardiac renin-angiotensin system.8 9 10
ACEIs prevent LVH in vivo, even at doses that do not significantly reduce blood pressure.11 12 13 The mechanisms of action of ACEIs are therefore not solely attributable to reductions in afterload. Additional mechanisms of action include block of ACE-mediated conversion of angiotensin I to Ang II and/or block of BK degradation.14 15 The degree to which ACEIs block the conversion of angiotensin I to Ang II in the heart is unclear. In the human heart, local formation of Ang II is predominantly attributed to an ACEI-insensitive chymase. This chymase does not modify BK.16 17 18 Recent evidence suggests a prominent role for BK in mediating the effects of ACEIs. The specific B2-kinin receptor antagonist Hoe 140 abolished the antihypertrophic effects of ACEIs, suggesting that tissue accumulation of BK, rather than diminished Ang II, is the effector of ACEI action.12
B2-kinin receptors were recently characterized on
VCMs, suggesting that BK could potentially have a direct effect on
cardiomyocytes.19 20 There is little
information currently available concerning the effect of BK on
hypertrophy of VCMs, especially in myocytes from mature
animals. Indirect evidence suggests BK may be hypertrophic, on the
basis of characteristics that are similar to other hypertrophic
agonists, including Ang II, 
1-adrenergic
receptor agonists, and endothelin-1.21 22 23 24 This
evidence includes the following (1) the B2-kinin
receptor is a "serpentine" receptor that is coupled to G proteins;
(2) inositol-1,4,5-triphosphate is increased by
BK19 20 25 ; (3) BK activates protein
kinase C25 26 ; and (4) BK activates the
mitogen-activated protein kinase
cascade.25 27
Because the ECs adjacent to the myocytes may play a role in the anti-hypertrophic effects of ACEIs, the objectives of the present study were (1) to determine whether BK, acting via the B2-kinin receptor, directly induces hypertrophy in both neonatal and adult myocytes and (2) to test the hypothesis that ECs play a role in blocking hypertrophy induced by BK and Ang II.
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Methods |
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Isolation of Adult Rat VCMs
VCMs from adult male Sprague-Dawley rats weighing 200 to 250 g were isolated as previously described.28 In brief, myocytes were freshly dissociated and plated onto laminin-coated (Collaborative Biomedical Products) six-well plates (Falcon; Becton Dickinson) in serum-free medium 199 (with Earle’s salts, 25 mmol/L HEPES, and bicarbonate without glutamine; Sigma Chemical Co). The medium was supplemented with 0.2% bovine serum albumin, 2 mmol/L L-carnitine, 5 mmol/L creatine, 5 mmol/L taurine, and 5 µg/mL gentamicin (Sigma) and 100 U/mL penicillin and 69 µmol/L streptomycin (Gibco BRL/Life Technologies). VCMs were incubated at 37°C until required for use in experiments (2 to 24 hours), with <7% nonmyocyte contamination, as previously described.28 Density of viable adult myocytes was
5 to 7.5x104 cells/35-mm well at time of
harvest. The treatment of animals used in this study was in accordance
with institutional guidelines.
Cultured Neonatal Rat VCMs
Neonatal rat VCMs from 2- to 3-day-old Sprague-Dawley rats were
obtained as previously described.29 Myocytes were
plated to subconfluence onto six-well plates (Falcon; Becton
Dickinson). DMEM, with L-glutamine, HEPES, and sodium
pyruvate, was supplemented with 7% fetal bovine serum, 1000 U/mL
penicillin, and 690 µmol/L streptomycin (Gibco) and 25 µg/mL
gentamicin (Sigma). After 24 hours in serum, VCMs were incubated at
37°C in serum-free DMEM (DMEM supplemented with 0.2% bovine serum
albumin, 25 µg/mL gentamicin (Sigma), 1000 U/mL penicillin,
and 690 µmol/L streptomycin), for a minimum of 48 hours. Density
of viable neonatal myocytes was 5x105
cells/35-mm well at time of harvest, with <7% nonmyocyte
contamination, as previously described.29
Cardiac-Derived ECs
Rat heart–derived ECs were established and maintained as
previously reported30 in DMEM supplemented with
7% fetal bovine serum, 1000 U/mL penicillin, 690 µmol/L
streptomycin, and 50 µg/mL gentamicin. Passage levels of 20 to 40
were used for this study. ECs were plated onto 0.45-µmx30-mm mixed
cellulose ester culture plate inserts (Millipore) and incubated at
37°C until confluent. Immediately before study, these inserts were
washed with serum-free medium 199 (described above) and placed onto
six-well plates containing adult rat VCMs. The same medium containing
[3H]phenylalanine with or without study drug(s)
was added to wells containing VCMs and to the EC-coated inserts. The
membrane of these inserts rested 1 mm above the myocyte
monolayer.
ANP Release
For neonatal VCMs, at the end of the incubation period with
study compounds, myocytes were washed twice with serum-free DMEM before
a further 1-hour incubation at 37°C. Aliquots of the cell culture
supernatant were then taken, and de novo release of ANP per hour was
determined by radioimmunoassay.31 Neonatal VCMs
were then harvested (see below). DNA content of wells was determined
with the use of a dsDNA fluorescent quantification reagent
(PicoGreen, Molecular Probes Inc). Results for ANP release were then
expressed relative to nanograms of DNA to correct for cell number.
ANP RNA Expression
Total RNA from VCMs was extracted by use of RNA STAT-60 reagent
(Tel-Test "B", Inc) according to the vendor’s instructions.
Precipitated RNA was washed with 75% ethanol and resuspended in 0.1%
diethyl pyrocarbonate–treated water and stored at -70°C. RNA
concentrations were determined spectrophotometrically at 260 nm.
For the measurement of mRNA levels of ANP and GAPDH, complementary
oligonucleotides were synthesized with a 10-nt random
extension on the 3' ends. The 40-mer sequence of synthesized
oligonucleotide probe for rat ANP was
5'-GGACACCGCACTG TATACGGGATTTGCTCCGGAGTAGAAG-3' and the 50 mer
sequence for rat GAPDH was
5'-GGTGGAAGAATGGGAGTT GCTGTTGAAGTCACAGGAGACAGTCAGAGTAT-3'. The ANP
oligonucleotide protected 30 nt of ANP mRNA (nt 131
through 160; GenBank accession No. M27498). The GAPDH
oligonucleotide protected 40 nt of GAPDH mRNA (nt 908
through 947; GenBank accession No. X02231). The probes were 5' end
labeled with [
-32P]ATP (specific activity,
6000 Ci/mmol) by use of a polynucleotide kinase kit
(Gibco). The probes were purified by electrophoresis on a 8%
denaturing polyacrylamide gel.
For mRNA quantification, we used a commercially available S1 nuclease protection assay kit (S1-Assay, Ambion Inc). Samples containing 10 or 1 µg of total RNA were hybridized with 5x104 cpm of ANP or 5x104 cpm of GAPDH oligonucleotides, respectively. After denaturation at 90°C for 5 minutes, hybridization was performed overnight at 25°C. S1 nuclease (75 U) digestion was performed for 60 minutes at 37°C. The resulting nucleic acid precipitate was dissolved in 12 µL of 80% formamide loading buffer and electrophoresed on a denaturing 8% polyacrylamide gel. After electrophoresis, the gel was dried and placed in a cassette for analysis by use of a PhosphorImager and ImageQuant software (Molecular Dynamics). The gel was autoradiographed after computer analysis. The PhosphorImager results were expressed as ratios of ANP mRNA to GAPDH mRNA.
[3H]Phenylalanine Incorporation
We incubated adult VCMs with
L-[2,3,4,5,6-3H]phenylalanine (1.5
µCi/mL, specific activity 132 Ci/mmol; Amersham Corp) with or without
study drug(s) and with or without inserts plated with ECs at 37°C.
Medium 199 contained 303 µmol/L unlabelled
DL-phenylalanine. At the end of a 2-hour incubation period,
the myocytes were thoroughly washed with ice-cold phosphate-buffered
saline (pH 7.4). The protein and DNA were precipitated with 10%
trichloroacetic acid for 1 hour at 4°C. Each well was then scraped
and the precipitate washed with 95% ethanol. The resulting pellet was
resuspended in 0.15 mol/L sodium hydroxide.
[3H]Phenylalanine incorporation was determined
by scintillation counting an aliquot of each sample. Results were
normalized to nanograms of DNA/well to correct for cell number.
Neonatal VCMs were incubated with
[3H]phenylalanine (0.44 µCi/mL; Amersham
Corp) with or without study drug(s) at 37°C. DMEM contained 400
µmol/L unlabeled L-phenylalanine. At the end of the
48-hour incubation period, the myocytes were harvested in the same
manner as described above for the adult VCMs.
Solutions containing BK were supplemented with lisinopril (1 µmol/L), a concentration shown to limit BK degradation in EC monolayers.15
Materials
Ang II, lisinopril, and PE were purchased from
Sigma, and BK was purchased from Research Biochemicals International.
Hoe 140 (Icatibant acetate) and losartan were kindly donated by
Hoechst Marion Roussel and Du Pont Merck Pharmaceuticals,
respectively.
Data Analysis
Each individual experiment was conducted with six replicates and
normalized for DNA content of each replicate. Experiments were repeated
5 to 14 times in different cell cultures. Results are expressed as
mean±SE. Statistical comparisons with the control were made by use of
the Wilcoxon signed rank test. The null hypothesis was rejected
at the P<.05 level. The Bonferroni correction for multiple
comparisons was applied where appropriate.
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Results |
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Determination of Optimum BK Concentration
To test the hypothesis that BK has a direct hypertrophic effect in adult and neonatal rat VCMs, we determined the influence of BK on markers of hypertrophy. To determine the appropriate concentration of BK, we conducted an initial concentration/response experiment. Fig 1 shows incorporation of [3H]phenylalanine by adult VCMs in response to BK over the concentration range of 0.01 to 10 µmol/L. It was apparent that a modest hypertrophic response was observed at 1 µmol/L but that the response at 10 µmol/L was more marked. Therefore, the concentration of BK chosen for study was 10 µmol/L. Preliminary experiments also indicated that(1) the optimum [3H]phenylalanine incorporation response of neonatal VCMs to Ang II and PE was a 48-hour incubation after at least 48 hours in serum-free medium, and (2) adult VCMs responded maximally to these agonists at 2 hours (data not shown). Thus, protein synthesis in adult VCMs was studied over a 2-hour period. In neonatal VCMs, protein synthesis and ANP expression was determined over a 48-hour period and de novo ANP release in the subsequent 60 minutes. All solutions containing BK were supplemented with lisinopril (1 µmol/L) to limit BK degradation.15 Lisinopril alone did not influence protein synthesis; [3H]phenylalanine incorporation in adult VCMs in its presence was 100±5% of control (n=3).
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BK Is Hypertrophic in Neonatal Cardiomyocytes
BK increased [3H]phenylalanine
incorporation by 36±10% (Fig 2A) and
ANP release by 357±103% (Fig 2B) in neonatal VCMs. Similarly, the
well-established hypertrophic agonists PE (20 µmol/L) and Ang II
(1 µmol/L) elicited increases of 36±6% and 26±3%,
respectively, in [3H]phenylalanine
incorporation (Fig 2A). Furthermore, ANP release by neonatal VCMs was
increased by PE and Ang II by 215±96% and 148±60%, respectively
(Fig 2B). The increases in [3H]phenylalanine
incorporation and ANP release induced by BK or Ang II were abolished by
the B2-kinin receptor antagonist Hoe
140 (10 µmol/L) or the angiotensin type 1 receptor
antagonist losartan (1 µmol/L),
respectively. The antagonists alone had no effect (results
not shown).
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ANP mRNA was quantified in neonatal VCMs after 48 hours’ incubation with BK (10 µmol/L in the presence of 1 µmol/L lisinopril), Ang II (1 µmol/L), or PE (20 µmol/L) in two independent studies. The autoradiogram from the first experiment is shown in Fig 3, and the results from both experiments are shown in the Table. BK increased ANP mRNA to a similar extent as Ang II.
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BK Is Hypertrophic in Adult Cardiomyocytes
BK (10 µmol/L) also increased protein synthesis in adult
VCMs (Fig 4);
[3H]phenylalanine incorporation was increased
by 23±3%. For comparison, PE (20 µmol/L) and Ang II (1
µmol/L) elicited increases of 33±3% and 24±3%, respectively (Fig 4). Hoe 140 (10 µmol/L) or losartan (1 µmol/L)
blocked the BK- and Ang II–mediated increases in
[3H]phenylalanine incorporation, respectively.
The antagonists alone had no effect (results not
shown).
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Interaction Between Ang II and BK in Adult Myocytes
The second objective of the present study was to test the
hypothesis that ECs contribute significantly to BK-induced prevention
of hypertrophy. Subsequent studies were conducted to test
this hypothesis. In the absence of ECs, BK (10 µmol/L) did not
block the increase in protein synthesis induced by Ang II (1
µmol/L). [3H]phenylalanine incorporation in
the presence of Ang II and BK was 119±3% of control (Fig 5A).
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To determine the effect of ECs on modulation of hypertrophy by BK, adult VCMs were cultured with ECs in a noncontact culture system. In this model, BK did not increase protein synthesis; [3H]phenylalanine incorporation was 94±3% of control (Fig 5B). Conversely, the increase in protein synthesis by adult VCMs induced by Ang II was preserved in the presence of ECs ([3H]phenylalanine incorporation was 122±2% of control; Fig 5B). However, when Ang II and BK were studied in combination, BK completely abolished the hypertrophic effect of Ang II in these coculture studies. Blockade of B2-kinin receptors with Hoe 140 restored the hypertrophic response to Ang II (Fig 5B).
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Discussion |
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Three important concepts emerge from this study. First, BK has a direct hypertrophic effect on VCMs. Second, ECs block the hypertrophic response to BK, suggesting that ECs release a factor or factors that inhibit BK-induced hypertrophy. Third, Ang II–induced hypertrophy is also blocked by BK-stimulated ECs, suggesting that inhibition of Ang II production at the tissue level may not be required for ACEIs to be effective in blocking hypertrophy. These results also emphasize the need for normally functioning ECs for maximal ACEI efficacy.
Previously, BK has not been recognized to be a potent hypertrophic agonist, particularly in the physiologically relevant adult cardiomyocyte. We found that BK increased protein synthesis, ANP release, and ANP mRNA similar to Ang II. The finding that BK was a hypertrophic agonist was predictable given the ability of BK to elicit "serpentine" receptor–activated, G-protein–coupled phosphatidylinositol-4,5-biphosphate hydrolysis19 20 25 27 32 and MAP kinase cascade activation27 similarly to known hypertrophic agonists, including PE, endothelin-1, and Ang II.21 22 23 24 Because ACEIs increase tissue levels of BK,33 the mechanism by which ACEIs block the induction of ventricular hypertrophy must now include inhibition of hypertrophic changes induced by a direct effect of BK on the cardiomyocyte.
Recently, an equivocal hypertrophic effect of BK was found in cultured neonatal rat VCMs in spite of short-term activation of signaling pathways similarly invoked by PE and Ang II.25 In that study, there was no apparent attempt to diminish BK degradation over the 24- to 48-hour study period. BK is rapidly degraded in tissue culture in the absence of ACEIs.15 It is likely that the addition of an ACEI in our study prevented rapid degradation of BK, allowing us to detect an effect of BK after extended periods of incubation.
We have made the distinctive observation that coculture of adult cardiomyocytes with ECs abolished the hypertrophic effects of BK and Ang II. The mechanism by which ECs mediate this effect in response to BK is not known. Candidate paracrine mediators include nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor, which are known to be released from ECs in response to BK.34 35 36 The present study illustrates the importance of intact, normally functioning ECs in blocking the hypertrophic effect of BK. Because ACEIs increase tissue levels of BK, the present study suggests that normally responsive ECs are required to inhibit the direct hypertrophic effect of BK on VCMs in individuals treated with these drugs. There is evidence that individuals with heart disease have a diseased cardiac endothelium.37 38 ACEIs may be beneficial in these individuals by reducing afterload; however, the direct beneficial effects of ACEIs on the heart may be diminished if EC dysfunction exists.
ACEIs have proved highly effective in the treatment of LVH within the context of ventricular remodeling.39 40 The mechanism by which ACEIs mediate their effects on the heart is unclear. Until recently, the presumed mechanism was inhibition of Ang II production. However, this notion has been brought into question by the observation that another enzyme in the human heart has the capacity to convert angiotensin I to Ang II, a chymase that is ACEI insensitive.16 17 18 Furthermore, in recent studies the antihypertrophic and other beneficial effects of ACEIs have been found to be blocked by the B2-kinin receptor antagonist Hoe 140.12 41 42 These studies suggest that elevated tissue levels of BK play an essential role in blocking the induction of hypertrophy. We have now demonstrated in the present investigation that BK has the ability to block Ang II–mediated hypertrophy, suggesting that inhibition of Ang II production may not be required to achieve the therapeutic benefits of ACEIs.
In conclusion, BK treatment of neonatal and adult rat VCMs augments protein synthesis, release of ANP, and ANP mRNA, markers of hypertrophy. In the presence of ECs, the hypertrophic effect of BK is abolished. Furthermore, BK also blocks Ang II–induced hypertrophy in the presence of ECs. The critical dependence of the antihypertrophic effect of BK on ECs suggests patients with some degree of endothelial dysfunction may have a diminished response to ACEI therapy.37 38 Our current findings strongly support an important role for BK in ACEI-induced inhibition of ventricular hypertrophy.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grant HL-54086 (J.D.M.), a grant from the Vascular Biology Training Program from the Department of Internal Medicine (J.D.M. and R.J.S.), and a grant from the Michigan Affiliate, American Heart Association (J.D.M.). Dr Ritchie is a Research Fellow in the Vascular Biology Training Program. The authors would like to thank Dr Amy J. Davidoff (Program in Molecular & Cellular Cardiology, Wayne State University) for providing the adult myocytes and Joanne Davis and Lisa Jefferson for technical assistance.
Received July 7, 1997; first decision July 28, 1997; accepted September 18, 1997.
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