The possible roles of mineralocorticoid receptor and 11β-hydroxysteroid dehydrogenase type 2 in cardiac fibrosis in the spontaneously hypertensive rat

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Abstract

In hypertension, aldosterone has been demonstrated to play a crucial role in cardiac fibrosis, which generally increases cardiac morbidity and death. However, few studies have reported the expression of the mineralocorticoid receptor (MR) and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in the heart under hypertensive conditions. Therefore, in this study, spontaneously hypertensive rats (SHR) were examined to elucidate the possible actions of mineralocorticoids via binding to MR. Wister Kyoto Rat (WKY), SHR, stroke-prone SHR (SHRSP), and malignant SHRSP (M-SHRSP) were used. Total RNA was extracted from the left ventricle of these rats, and examined for the expression levels of MR, 11β-HSD2 and Collagen types 1 and 3 using reverse transcription real-time quantitative polymerase chain reaction employing the Light Cycler Instrument. Blood pressure was significantly different among each group. The mean mRNA levels for MR, 11β-HSD2 and Collagen types 1 and 3 in M-SHRSP were found to be significantly increased compared to those of WKY, whereas no significant differences in mRNA levels were detected among SHR and SHRSP. Findings from the present study appear to demonstrate that MR and 11β-HSD2 mRNA significantly rise in the left ventricle of M-SHRSP and increase of these mRNA is one of the cause of cardiac fibrosis.

Introduction

In hypertension, left ventricular hypertrophy resulting from structural remodeling of the myocardium such as myocytic hypertrophy, intersititial fibrosis and structural alterations of the coronary microcirculation [1] have been shown to greatly contribute to cardiac morbidity and subsequent death of patients [2], [3], [4].

Myocardial fibrosis has always been associated with increased levels of circulating aldosterone or local stimulation of the renin–angiotensin–aldosterone system [5]. However, little is known on the correlation among other factors such as MR, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) which has been shown to protect MR from occupancy by glucocorticoids [6], [7], arterial blood pressure and cardiac fibrosis.

In the present study, we examined spontaneously hypertensive rats (SHR) which were classified based on the severity of hypertension, for the relative mRNA expression of MR, 11β-HSD2, and Collagen type 1 (Collagen 1) and Collagen type 3 (Collagen 3), both of which have been demonstrated to be closely associated with myocardial fibrosis [8] using semi-quantitative PCR.

Section snippets

Animals

Wister Kyoto (WKY), SHR, stroke-prone SHR (SHRSP) and malignant SHRSP (M-SHRSP) rats were employed in this study. These three strains of hypertensive rats were established from WKY [9]. The animals were bred and fed with the blood pressure of each strain carefully maintained at its respective fixed level in the Kinki University School of Medicine. Each animal was sacrificed at the age of 15 weeks, when the blood pressure achieved peak levels [10].

RNA isolation and cDNA synthesis

Total RNA was extracted by homogenizing frozen

Hypertension model

Blood pressure was significantly different among each group. (WKY: 139.6±2.7 mmHg; SHR: 177.2±6.1 mmHg; SHRSP: 218.6±32.7 mmHg; and M-SHRSP: 255.6±8.8 mmHg).

Expression of MR mRNA

The average level of MR mRNA in M-SHRSP increased significantly (12.3-hold) compared to that of WKY, whereas SHR and SHRSP did not, as shown in Fig. 1 (P=0.0011, Kruskal-Wallis; P=0.0090, Mann–Whitney U test).

Expression of 11β-HSD2 mRNA

Fig. 2 demonstrated that 11β-HSD2 mRNA yielded a similar pattern with respect to MR mRNA. The average levels of 11β-HSD2 in M-SHRSP were

Discussion

The present study demonstrated that MR mRNA increased steeply in the left ventricle of M-SHRSP (Fig. 1), which has been reported to have significantly high plasma aldosterone concentration [11]. Aldosterone produces a dose-dependent increase of MR and its mRNA levels in cultured primary hippocampal neurons [12]. Therefore, the presence of positive feedback mechanism of aldosterone to MR expression may take place in the heart.

11β-HSD2 mRNA also increased in the same manner as MR mRNA (Fig. 2).

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Presented at the 11th International Congress on Hormonal Steroids and Hormones and Cancer, ICHS & ICHC, Fukuoka, Japan, 21–25 October 2002.

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