Elsevier

Peptides

Volume 28, Issue 7, July 2007, Pages 1383-1389
Peptides

Differential role of kinin B1 and B2 receptors in ischemia-induced apoptosis and ventricular remodeling

https://doi.org/10.1016/j.peptides.2007.05.010Get rights and content

Abstract

We investigated the role of kinin receptors in cardiac remodeling after ischemia/reperfusion (I/R). Bradykinin injection improved cardiac contractility, diastolic function, reduced infarct size and prevented left ventricular thinning after I/R, whereas des-Arg9-BK injection had no protective effects. Bradykinin, but not des-Arg9-BK, reduced cardiomyocyte apoptosis and increased Akt and GSK-3β phosphorylation. Furthermore, myocardial infarct size was similar between wild type and B2 knockout mice after I/R, but significantly reduced in kinin B1 receptor knockout mice. These results indicate that the kinin B2 receptor, but not the B1 receptor, protects against I/R-induced cardiac dysfunction by inhibiting apoptosis and limiting ventricular remodeling.

Introduction

The responses to vasoactive kinin peptides are mediated by the activation of bradykinin receptor B1 (B1R) and B2 (B2R) according to the relative potencies and affinities to their agonists [14]. B2R is constitutively expressed in most tissues and responsive to intact bradykinin (BK) and kallidin (Lys-BK). In contrast, B1R which has a higher affinity for des-Arg9-BK (DBK) and des-Arg10-kallidin, is weakly expressed under physiological conditions but induced by pathological stimuli such as inflammation and tissue injury [15]. BK through B2R activation has been shown to limit infarct size in the ischemic heart in the late phase of preconditioning [8]. In contrast, B1R might play a detrimental role in the ischemic heart after IR, as infarct size was significantly reduced in B1R−/− mice compared with wild-type mice after myocardial infarction (MI), and administration of B1R antagonist significantly reduced ischemic injury in wild-type mice [10]. Paradoxically, another study demonstrated that B1R−/− mice had a larger LV diastolic chamber dimension initially and after 4–8 weeks compared with wild-type mice after MI, indicating that B1R may play protective role in regulation of structural homeostasis at the early stage after cardiac injury [20]. However, the cardioprotective role of B1R is uncertain because this study demonstrated a similar degree of myocardial injury and remodeling between wild-type mice and B1R−/− mice after myocardial infarction. Furthermore, B2R has been implicated in accentuation of infarction-induced inflammation as blockade of B2R by an antagonist after MI exerts no effect on infarct size after MI but attenuates inflammatory cell reaction both inside and outside infarct area, thus resulting in reduction of fibrosis and collagen deposition [7]. Therefore, the role of B2R and B1R in the ischemic myocardium after MI remains to be further investigated.

In this study, we compared the effects of B1R and B2R agonists on cardiac function, cardiomyocyte apoptosis and LV remodeling in short and long-term I/R models of rats. In addition, we investigated the role of B1R and B2R in cardiac remodeling using B1R and B2R knockout mice. Using both pharmacological approaches and genetic animal models, our results demonstrate that kinin B2 receptor, but not B1 receptor, activation preserves cardiac function by inhibiting apoptosis and limiting deteriorated left ventricular remodeling after I/R is associated with Akt and GSK-3β phosphorylation.

Section snippets

Animals

Wistar rats (male, 240–260 g, Sprague–Dawley Harlan, Indianapolis, IN) were employed in this study. All procedures complied with the standards for care and use of animal subjects as stated in the Guide for the Care and Use of Laboratory Animals (National Academy of Sciences, Bethesda, MD). Two breeding pairs of B1 kinin receptor knockout mice (B1R−/−) on a C57/J6 genetic background were obtained from Dr. Michael Bader's laboratory (Max-Delbrück Center for Molecular Medicine, Berlin-Buch,

BK, but not DBK, reduces infarct size and improves cardiac function after acute I/R

Table 1 shows the effects of BK and DBK on cardiac function after 24-h reperfusion. HR and MAP were not changed among all groups. BK injection significantly improved impairments in contractility (dP/dtmax) and diastolic function (LVEDP and dP/dtmin) after I/R, but DBK did not exert any protective effects. Moreover, representative TTC staining at 1 day after I/R showed that treatment with BK but not DBK reduced myocardial infarct size as compared to I/R control (Fig. 1A). Quantitative analysis

Discussion

In the present study, we demonstrated that the kinin B2 receptor, but not B1, receptor exerts cardioprotective effects against myocardial I/R injury by using both pharmacological approaches and genetic animal models. Our results show that administration of BK, but not DBK, attenuates cardiomyocyte apoptosis, reduces infarct size and improves cardiac function and remodeling in rats after I/R injury. Furthermore, the anti-apoptotic effect of BK is correlated with increased Akt and GSK-3β

Acknowledgements

This work was supported by National Institutes of Health grants HL29397, DK066350 and C06 RR015455 from the Extramural Research Facilities Program of the National Center for Research Resource.

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