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CLINICAL STUDY: HYPERTENSION

Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in hypertension due to endogenous angiotensin II

Teresa M. Seccia, MD^*, Anna S. Belloni, BSc, Reinhold Kreutz, MD, Martin Paul, MD, Gastone G. Nussdorfer, MD, Achille C. Pessina, MD, PhD and Gian Paolo Rossi, MD, FACC^,*

^* Department of Clinical Methodology and Clinical-Surgical Technologies, University of Bari, Bari, Italy
Department of Human Anatomy and Physiology (Section of Anatomy), University of Padova, Padova, Italy
Institute of Clinical Pharmacology and Toxicology, Freie University of Berlin, Berlin, Germany
Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Padova, Italy

Manuscript received June 19, 2002; accepted October 17, 2002.

^* Reprint requests and correspondence: Dr. Gian Paolo Rossi, Dept. of Clinical and Experimental Medicine, Clinica Medica 4, University Hospital, via Giustiniani, 2, 35126 Padova, Italy.
gianpaolo.rossi{at}unipd.it

OBJECTIVES: We investigated if endothelin (ET)-1 and the renin-angiotensin-aldosterone system play a role in cardiac fibrosis.

BACKGROUND: Angiotensin II (Ang II) can induce cardiac fibrosis, but the underlying mechanisms are incompletely understood.

METHODS: Four-week-old transgenic (mRen2)27 rat (TGRen2) received for four weeks a placebo, the mixed ET_A/ET_B endothelin receptor antagonist bosentan, the angiotensin II type I receptor (AT-1) antagonist irbesartan, the ET_A endothelin receptor antagonist BMS-182874, and a combined treatment with irbesartan plus BMS-182874. We measured collagen density on Sirius red–stained serial sections of the left ventricle (LV) with a photomicroscope equipped with specific software and assessed the gene expression of procollagen 1(I), atrial natriuretic peptide (ANP), transforming growth factor-beta 1 (TGFß1), endothelin converting enzyme, and ET_B receptor.

RESULTS: In the placebo group, hypertension was associated with LV hypertrophy and cardiac fibrosis (LV weight: 4.0 ± 0.3 mg/g body weight; collagen density: 2.21 ± 0.16%), which were all prevented with irbesartan (2.3 ± 0.1, 1.30 ± 0.13, p < 0.001), but not with BMS-182874 (4.0 ± 0.2, 2.41 ± 0.22). Bosentan also prevented fibrosis (1.39 ± 0.18) but not hypertension and LV hypertrophy (3.38 ± 0.27). Combined irbesartan and BMS-182874 treatment prevented LV hypertrophy (2.9 ± 0.1) but not fibrosis (2.52 ± 0.16). Collagen density correlated (r = 0.414, p < 0.05) with plasma aldosterone levels. In TGRen2 with LV hypertrophy, the gene expression of ANP and ET_B but not that of TGFß1 and procollagen 1(I) was increased.

CONCLUSIONS: In Ang II–dependent hypertension, cardiac fibrosis was associated with LV hypertrophy and was hindered by both mixed ET_A/ET_B blockade and AT-1 blockade. Only the latter treatment prevented both hypertension and LV hypertrophy. Thus, there is a dissociation between the mechanisms of cardiac fibrosis and hypertension, which do and do not entail ET-1, respectively.

Abbreviations and Acronyms   Ang II   angiotensin II   ANP   atrial natriuretic peptide   AT-1   angiotensin II type I receptor   BP   blood pressure   BW   body weight   DOCA   deoxycorticosterone acetate   ET-1   endothelin-1   LV   left ventricle   RAAS   renin-angiotensin-aldosterone system   TGFß1   transforming growth factor-beta 1   TGRen2   transgenic (mRen2)27 rat   2K1C   2 kidney 1 clip model

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