Regulation of cardiac bradykinin B1- and B2-receptor mRNA in experimental ischemic, diabetic, and pressure-overload-induced cardiomyopathy

Regulation of cardiac bradykinin B1- and B2-receptor

mRNA in experimental ischemic, diabetic, and

pressure-overload-induced cardiomyopathy

Frank Spillmann 1, Christine Altmann 1, Michael Scheeler, Marcos Barbosa,Dirk Westermann, Heinz-Peter Schultheiss, Thomas Walther, Carsten Tschope*

Department of Cardiology and Pneumology, University Hospital Benjamin Franklin, Free University of Berlin,

Hindenburgdamm 30, D-12220 Berlin, Germany

Abstract

Although kinins have been associated with the regulation of cardiovascular function in left ventricular hypertrophy (LVH) as

a consequence of hypertension, myocardial infarction (MI), and/or diabetic cardiomyopathy, less is known about their receptor

regulation under these conditions. We have therefore investigated the bradykinin B1-receptor (B1R) and B2-receptor (B2R)

mRNA expression in rat models of MI, LVH and diabetes mellitus (DM).

Sprague–Dawley rats (SD) were submitted to permanent ligation of the left descending coronary artery (LAD) to induce a MI,

whereas DM was induced by a single injection of streptozotocin (STZ). LVH was induced after thoracic aortic banding (AB).

Three weeks after MI, six weeks after STZ injection or six weeks after AB, left ventricular (LV) function was characterized using a

Millar-tip catheter. Cardiac B1R- and B2R-mRNA expression were analyzed by specific RNase-protection assays (RPA).

LV contractility (dP/dt max) was impaired by 40–48% in rats after induction of MI or DM compared to their controls.

However, despite an enormous increase in LVend-diastolic pressure (LEVDP) to 310% after AB, LV contractility did not differ

compared to the controls. These hemodynamic changes were accompanied by an up-regulation of cardiac B1R- (MI, 288%; STZ,

215%; AB, 4180%) and B2R-mRNA expression (MI, 122%; STZ, 288%; AB, 96%).

Up-regulation of both BK-receptor (BKR) types in early stages of cardiac wound healing induced by ischemia and in chronic

stages of cardiac remodeling induced by pressure-overload or by hyperglycemia indicates that kinins play a major role in the

complex processes of cardiac tissue injury and repair.

D 2002 Elsevier Science B.V. All rights reserved.

Keywords: Bradykinin; B1 receptor; B2 receptor; Myocardial infarction; Aortic banding; Streptozotocin; Diabetes mellitus

1. Introduction

Kinins are important peptide mediators of a diverse

range of physiological and pathological functions of

the cardiovascular system [1]. They exert their bio-

logical effects by the selective stimulation of two

distinct G-protein-coupled receptors termed bradyki-

nin (BK) B1-receptor (B1R) and B2-receptor (B2R).

The principal kinin peptides involved in the acute

regulation of cardiovascular function during normal

physiology are bradykinin (BK) and Lys-BK, which

produce their effects via activation of the B2R [2]. In

cell culture experiments, B2R responds to its stimula-

1567-5769/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved.

PII: S1567 -5769 (02 )00174 -1

* Corresponding author. Tel.: +49-30-8445-2343; fax: +49-30-

7871-7823.

E-mail address: [email protected] (C. Tschope).1 Both authors contributed equally to this work.

www.elsevier.com/locate/intimp

International Immunopharmacology 2 (2002) 1823–1832

tion with a short strong signal, but it is also charac-

terized by an immediate and rapid loss of functional

response, receptor internalization and mRNA, and

protein down-regulation. The B1R, which is de novo

synthesized under stress conditions, is activated by the

des-Arg kinin metabolites des-Arg BK and Lys-des-

Arg BK. However, the ligand stimulation does not

comprise B1R internalization or desensitization, con-

sequently leading to persistent signalling [3].

Under basal conditions, the constitutive expressed

B2R mediate most, if not all, of the effects usually

attributed to kinins. In contrast, the effects mediated

by the B1R are largely unknown, and the results of

studies concerning their cardioprotective effects are

inconsistent [4].

Recent work with experimental animals suggests

that kinins have both short-term and long-term car-

dioprotective effects. The short-term cardioprotective

effects include protection of the myocardium from

ischemia–reperfusion injuries, whereas the long-term

effects involve the reduction of left ventricular hyper-

trophy (LVH) and the progression of heart failure

[5,6]. However, the regulation of the BK-receptor

(BKR) subtypes involved is largely unknown.

mRNA expression of both BKR can be up-regulated

by cytokines and oxidative stress [7,8] or may also

dependent on the status of other peptide systems like

the renin–angiotensin system (RAS) [1,9,10]. In the

present study, we verify this concept by investigating

cardiac BKR regulation in different rat models with

cardiac failure, known also to be characterized by an

activated cytokine cascade and up-regulated RAS.

Thus, we have determined the influence of ischemic

stress after the induction of myocardial infarction (MI),

metabolic stress after induction of diabetes mellitus

(DM) and of mechanic stress after pressure-overload-

induced left ventricular hypertrophy (LVH) on cardiac

B1R- and B2R-mRNA levels.

2. Methods

2.1. Animals and experimental protocols

MI and DM were induced in male Sprague–

Dawley (SD) rats weighing 300–330 g, whereas

aortic binding (AB) surgeries were performed in male

SD rats weighing 80–100 g (Charles Rivers, Ger-

many; n = 12 per group). The animals were allowed

unhindered access to water and standard fodder under

a 12 h light/dark cycle.

2.2. Surgical procedures

(a) Induction of myocardial infarction

MI was induced by permanent ligation of the left

descending coronary artery (LAD) as previously

described [11]. In brief, after induction of anaesthesia

with ketamine (50 mg/kg; Parke Davis, Germany) and

xylasine 2% (5 mg/kg; Medistar, Germany), the rats

were intubated and artificially ventilated (Respirator:

Ugo Basile (Type 7025), FMI, Germany) (n = 6). After

thoracotomy, the LAD was occluded using sterile 6–0

suture material (Ethibond, Ethicon, Germany). In the

rats that underwent sham surgery, ligatures were placed

beside the LAD (n = 6).

(b) Induction of diabetes mellitus

DM was induced by a single intraperitoneal injec-

tion of STZ (70 mg/kg, diluted in 0.4 ml sodium citrate

buffer (0.1 M, pH 4.5); Sigma, Munchen, Germany),

and hyperglycemia was confirmed 48 h later by a

reflectance meter (Acutrend, Boehringer Mannheim,

Germany) as previously described [12]. Only rats with

blood glucose levels of more than 300 mg/dl 3 days

after STZ injection were used (n = 6). Rats treated with

a single intraperitoneal injection of vehicle (n = 6) were

used as controls.

(c) Induction of left ventricular hypertrophy

Cardiac hypertrophy was elicited by AB as pre-

viously described [13]. After anaesthesia, artificially

controlled ventilation, and thoracotomy, a 0.6-mm

clip was placed around the ascending aorta of 4-

week-old rats (f 100 g body weight) (n = 6). Control

animals underwent identical surgery without place-

ment of the clip. AB and control (sham) animals were

studied at 6 weeks post-surgery (n = 6).

2.3. TIP catheter measurements

All groups were compared with time-matched

sham-operated controls. Left ventricular (LV) peak

F. Spillmann et al. / International Immunopharmacology 2 (2002) 1823–18321824

systolic pressure (LVP, in mmHg), LV end-diastolic

pressure (LVEDP, in mmHg), the maximal rate of

LV pressure rise (dP/dt max, in mmHg/s) as a

measure of LV systolic contraction and the minimal

rate of LV pressure fall (dP/dt min, in mmHg/s) as a

measure of LV systolic relaxation were recorded via

a Millar-tip catheter (2F) system in anaesthetized,

ventilated, open-chest animals at the end of the

study [14].

After the experiment, the hearts were excised and

the LV was macroscopically separated for mRNA

analysis of B1R and B2R expression. LV was rapidly

frozen in liquid nitrogen and stored at � 80jC.

2.4. Molecular–biological investigations

(a) RNA isolation

Total RNA was isolated after homogenization of

the LV in six animals per group using Trizol reagent

(Gibco, Germany) following the manufacturer’s direc-

tions.

(b) Ribonuclease protection assay

To detect myocardial B1R and B2R expression,

RNase-protection assays (RPA) were performed as

Fig. 1. B1-receptor mRNA expression in the left ventricle (LV) 3 weeks after induction of myocardial infarction (MI) or after sham operation.

(A) Representative RNase-protection assay (n= 4 each group) showing B1-receptor (192 and 257 bp) vs. rL32 (127 bp) expression. (B)

Quantification of B1-receptor expression after autoradiographic signal analysis. Data are shown as multiples after normalization to rL32 mRNA

levels (n= 6), *P< 0.05 vs. sham.

F. Spillmann et al. / International Immunopharmacology 2 (2002) 1823–1832 1825

previously described [11,14] using the Ambion RPA

II kit (ITC Biotechnology, USA). Anti-sense RNA

probes were generated by T7 polymerase transcription

using linearized plasmids containing fragments of

B1R or B2R cDNA, and GAPDH or rL32 cDNA

probes as an internal control. The probes were radio-

labeled with [32P]UTP and approximately 5� 104

c.p.m. from each probe were hybridized together with

25 mg (B1R) or 18 Ag (B2R) of total RNA per

sample. After RNase A/T1 digestion, 257 bp (exon

1 and exon 2) and 192 bp (exon 2) from the B1R

cDNA, 274 bp (intron 3 and exon 4) and 221 bp (exon

4) from the B2R cDNA, as well as 130 or 127 bp from

control GAPDH or rL32 sequences, respectively, were

protected. The hybridized fragments were separated

by electrophoresis on a denaturing gel and analyzed

using the FUJIX BAS2000 phosphor-imager system.

Quantitative analysis was performed by measuring the

intensity of the B1R and B2R bands normalized by

the band intensity of the housekeeping gene.

Fig. 2. B2-receptor mRNA expression in the left ventricle (LV) 3 weeks after induction of myocardial infarction (MI) or after sham operation.

(A) Representative RNase-protection assay (n= 4 each group) showing B2-receptor (221 and 274 bp) vs. rL32 (127 bp) expression. (B)

Quantification of B2-receptor expression after autoradiographic signal analysis. Data are shown as multiples after normalization to rL32 mRNA

levels (n= 6), *P< 0.05 vs. sham.


2.5. Statistical analysis of data

All data are expressed as meansF S.E.M., and

were analyzed by Student’s t-test. P values < 0.05

were accepted as significant.

3. Results

3.1. Left ventricular function after induction of

myocardial infarction

Three weeks after the induction of MI, the mean

LV infarct size was about 43%. LVP and systolic

contractility (dP/dt max) were reduced by 40–48%

and systolic relaxation (dP/dt min) and LVEDP were

increased by 49% and 56%, respectively, 3 weeks

after coronary occlusion as compared to controls.

3.2. Left ventricular function after induction of

diabetes mellitus

Throughout the 6-week study period, the STZ-

induced diabetic rats developed severe hyperglycemia

(620F 25.5 vs. 133F 13.2 mg/dl; P < 0.01). Thereby,

LVP and systolic contractility (dP/dt max) were

reduced by 40–43% and systolic relaxation (dP/dt

min) and LVEDP were increased by 40% and 26%,

respectively.

3.3. Left ventricular function after induction of left

ventricular hypertrophy

Six weeks after thoracic AB, the heart weight-to-

body weight ratio was increased 41.6F 3.3%.

Whereas LVP and systolic contractility (dP/dt max)

and systolic relaxation (dP/dt min) were slightly but

Fig. 3. B1-receptor mRNA expression in the left ventricle (LV) 6 weeks after induction of diabetes mellitus (SD STZ) or after sham application

(SD Co). (A) Representative RNase-protection assay (n= 4 each group) showing B1-receptor (192 and 257 bp) vs. GABDH (130 bp)

expression. (B) Quantification of B1-receptor expression after autoradiographic signal analysis. Data are shown as multiples after normalization

to GABDH mRNA levels (n= 6), *P < 0.05 vs. SD Co.


not significantly impaired, we found an expected

increase in LVEDP by 310% in these animals com-

pared to the controls. This degree of hypertrophy has

previously been shown not to elicit impaired contrac-

tile function [13].

3.4. Kinin receptor regulation after induction of

myocardial infarction

B1R- and B2R mRNA concentrations were meas-

ured in homogenates of isolated LV from sham-

operated and infarcted SD rats 3 weeks after surgery

(n= 6 per group).

In infarcted SD rats, B1R-mRNA expression was

increased by 288% (P < 0.05), and B2R-mRNA

expression by 122% (P < 0.05) compared to sham-

operated rats (Figs. 1 and 2).

3.5. Kinin receptor regulation after induction of

diabetes mellitus

B1R- and B2R-mRNA concentrations were meas-

ured in homogenates of isolated LV from sham-treated

and hyperglycemic SD rats 6 weeks after DM induction

(n = 6 per group). In diabetic SD rats, B1R-mRNA

expression was increased by 215% (P < 0.05), and

Fig. 4. B2-receptor mRNA expression in the left ventricle (LV) 6 weeks after induction of diabetes mellitus (SD STZ) or after sham application

(SD Co). (A) Representative RNase-protection assay (n= 4 each group) showing B2-receptor (221 and 274 bp) vs. GABDH (130 bp)

expression. (B) Quantification of B2-receptor expression after autoradiographic signal analysis. Data are shown as multiples after normalization

to GABDH mRNA levels (n= 6), **P< 0.005 vs. SD Co.


B2R-mRNA expression by 288% (P < 0.005) com-

pared to normoglycemic rats (Figs. 3 and 4).

3.6. Kinin receptor regulation after induction of left

ventricular hypertrophy

B1R- and B2R-mRNA levels were measured in

homogenates of isolated LV from sham-operated SD

rats and rats that underwent AB for 6 weeks (n = 6 per

group).

In sham-operated animals, B1R-mRNA was only

weakly expressed. Thus, the cardiac overload led to

an increase of B1R-mRNA by 4180% (P < 0.0001).

In contrast, B2R-mRNA showed a higher expression

under basal conditions and increased by 96%

(P < 0.05) compared to sham-operated rats (Fig. 5).

4. Discussion

All components of a functional kallikrein–kinin

system (KKS) are expressed in the heart, and kinins

clearly mediate important cardiovascular effects, such

as increased vascular dilation and permeability,

enhanced myocardial glucose uptake, negative ino-

tropism, and inhibition of myocardial growth [5].

Many, but not all, of these effects are secondary to

their ability to generate autacoids, such as nitric oxide

and prostaglandins after stimulation of B2R and/or

B1R. Under stress conditions, the regulation of both

BKR may differ compared to basal conditions. Thus,

pro-inflammatory cytokines like interleukin 1h and

tumor necrosis factor a (TNFa) [7,8], as well as

stimuli from different peptide systems, like the RAS,

Fig. 5. B1-receptor and B2-receptor mRNA expression in the left ventricle (LV) 6 weeks after supra valvular aortic banding (SD SVAB) or after

sham surgery (SD Sham). (A) Representative RNase-protection assay (n= 4 each group) showing B1-receptor (192 and 257 bp) and B2-receptor

(221 and 274 bp) vs. rL32 (127 bp) expression. (B) Quantification of B1- and B2-receptor expression after autoradiographic signal analysis.

Data are shown as multiples after normalization to rL32 mRNA levels (n= 6), *P< 0.05 vs. SD Co.


are involved in the regulation of these receptors

[1,9,10]. Although it is widely accepted that the

B1R in particular is up-regulated under stress con-

ditions, the individual expression pattern of both BKR

under different cardiovascular pathophysiological

conditions has not been studied in detail.

4.1. Kinin receptor regulation 3 weeks after induction

of myocardial infarction

After MI, increased plasma levels of kallikrein

(KLK), kininogen and BK were found [15,16], and

the increase in plasma KLK levels was positively

correlated with the early survival rate of post-MI

patients [17]. It has been shown that kinins are directly

released from the myocardium during MI [18], and

contribute to the impact of ischemic damage [17]. In the

present study, no regulation of the B1R or B2R expres-

sion has been found in time-matched sham-operated

rats, indicating that the surgery itself did not induce any

BKR regulation. In agreement with others, we found a

basal B2R but only a very weak B1R expression in the

LV of sham-operated rats [19]. Previously, we had

found that the B1R and B2R are up-regulated in the

early (6 and 24 h post-MI) as well as in the late-

inflammatory phase (6 days post-MI) of wound healing

after ischemia-induced tissue damage [6,11,14]. In this

current study, we reveal that likewise in the fibrogenic

phase (3 weeks post-MI) of tissue healing, both BKR

are still up-regulated in the ischemic LV compared to

the controls. A retrospective comparison of our data

with the results of our analyses performed at 24 h and 6

days post-MI allows us to conclude that 3 weeks post-

MI the BKR up-regulation revealed was much weaker

compared to the early time points. However, since all

these phases are characterized by an early increase in

cytokines like TNF and IL1h [7,8,20], as well as by an

activation of the RAS [1,9,10], both triggers may play a

role in ischemia-dependent BKR up-regulation.

Although no data are available for the role of the

B1R up-regulation post-MI, it has been shown that

pretreatment with the B2R antagonist icatibant leads

to a worsening of post-ischemic LV remodeling [21],

indicating the importance at least of the B2R-axis of

the KKS under this condition. This concept is also in

line with the observation that the cardiac anti-remod-

eling effects of an ACE inhibitor are reduced in B2R

knock-out mice after the induction of MI [22].


of diabetes mellitus

Diabetes mellitus (DM) is associated with the devel-

opment of myocardial dysfunction in the absence of

coronary artery disease, systemic hypertension, or

valvular heart disease [23]. Myocardial and vascular

integrity are profoundly altered in diabetic individuals

during the progression of diabetes. Some of these

changes may be related to an impaired endothelial

synthesis and release of vasoactive peptides [24],

involving the cardiac KKS. Several changes of the

cardiac KKS have been found under the diabetic

conditions that may contribute to the altered cardiac

function during the development of diabetic cardiopa-

thy [12,25]. The reduced effectiveness of exogenously

applied BK on vascular dilation has been reported in

diabetic subjects with endothelial dysfunction [26,27].

Preliminary data from our group indicate an improve-

ment in LV function of transgenic STZ-induced dia-

betic rats harboring the human KLK gene [28].

Moreover, we and others have previously described

reduced endogenous cardiac kininogen andKLK levels

and/or alterations in the activation of cardiac tissue

KLK in diabetic animals [12,25]. In our current study,

we found an increase in cardiac B1- and B2R-mRNA

levels 6 weeks after STZ injection. This is in agreement

with other studies, showing an early up-regulation of

both receptors in vessels and the spinal cord under

STZ-diabetic conditions [29–31]. Since the metabolic

stress induced under diabetic conditions is also accom-

panied by a stimulation of the RAS as well as of the

cytokine cascade [32], it is reasonable to suggest that

both these triggers may also play a role in BKR up-

regulation. However, a previous study by us found that

in pair-fed rats 13 weeks after STZ injection, the

cardiac B2R-mRNA levels are only slightly increased,

whereas the B1R-mRNA levels did not differ com-

pared to controls [12]. Thus, the changes in BKR-

mRNA regulation are time-dependent and may be

related to the state of the diabetic cardiopathy.


left ventricular hypertrophy

LVH substantially increases the risk of sudden

death and other cardiovascular complications even

after adjustment for other known risk factors [33].


Behind different polymorphisms of the RAS, it has

been shown that the + 9/� 9 B2R polymorphism may

also play a role in patients with LVH [34]. Thus, under

specific conditions, patients with low concentrations

of B2R ( + 9/ + 9 genotype) are thought to have an

increased risk of developing LVH, indicating the role

of the KKS in controlling LV mass.

However, cell culture studies of human and rat

fibroblasts have shown that BK can prevent the

effects of the proliferative stimuli of transforming

growth factor h, epidermal growth factor and platelet-

derived growth factor [35]. Furthermore, via B2R

stimulation, BK inhibits the hypertrophy of rat ven-

tricular myocytes induced by angiotensin II and by

phenylephrine [36]. These findings suggest that an

intact KKS is essential for the regulation of myocar-

dial growth. Indeed, it has been shown that B2R

knock-out mice develop LVH and heart failure [37].

Furthermore, transgenic rats overexpressing tissue

KLK develop less cardiac hypertrophy and fibrosis

than do wild-type rats [38]. Conversely, genetically

ablating B2 bradykinin receptors result in enhanced

salt-induced hypertension and hypertrophic cardio-

myopathy [37].

This concept is in agreement with our findings,

indicating that the mRNA levels of the cardiac B1R as

well as that of the B2R are up-regulated 6 weeks after

supravalvular constriction of the thoracic ascending

aorta. Thereby, we found especially an enormous

B1R-mRNA up-regulation, indicating that mechanical

stress is a very effective trigger for this receptor.

However, with respect to the cardiac B2R, this recep-

tor was found to be down-regulated in a mouse model

of abdominal aortic constriction between the right and

left Aa. renalis [39]. In contrast to our model, these

animals developed a renal hypertension (Goldblatt

hypertension: two kidneys–one clip), known to lead

to a massive stimulation of the systemic RAS.

Thereby the mechanical stress, indicated by the rise

in LVEDP is usually similar to that seen in rats after

induction in MI or DM. The model we used does not

lead to a prominent activation of the systemic RAS,

but is accompanied by an enormous increase in

LVEDP [40]. Although we cannot exclude that time-

dependent changes may also belong to these different

findings in BK2R-mRNA expression between thora-

cic and abdominal AB, we suggest that the degree of

mechanical stress and the status of additional triggers

like the RAS and/or cytokines play a role in BKR

regulation in cardiac failure.

We conclude that the up-regulation of both BKR

types during the development of cardiac remodeling

induced by pressure-overload-induced stress, by

hyperglycemia-induced oxidative stress as well as

after ischemia-induced stress indicates a major role

of kinins in the complex processes of cardiac tissue

injury and repair.

Acknowledgements

This study was supported by grants from the

Deutsche Forschungsgemeinschaft (DFG; TS-64/2-2).

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Regulation of cardiac bradykinin B1- and B2-receptor mRNA in experimental ischemic, diabetic, and pressure-overload-induced cardiomyopathy