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Extracellular signal regulated kinase and SMAD signaling both mediate the angiotensin II driven progression towards overt heart failure in homozygous TGR(mRen2)27

Abstract

Angiotensin (Ang) II is a key player in left ventricular (LV) remodeling and cardiac fibrosis. Its effects are thought to be transferred at least in part by mitogen-activated protein kinases (MAPK), transforming growth factor (TGF) β1, and the Smad pathway. In this study we sought to elucidate whether Ang II related effects on LV dysfunction and fibrosis in vivo are mediated via MAPK or rather via Smad stimulation. We treated homozygous REN2 rats (7–11 weeks) with placebo, Ang II type 1 (AT1) receptor blocker or tyrphostin A46 (TYR), an inhibitor of epidermal growth factor receptor tyrosine kinase that blocks extracellular signal-regulated kinase (ERK) activity. REN2 rats had LV hypertrophy (LVH) and LV dysfunction that progressed to heart failure between 10 and 13 weeks. Blood pressure normalized over time. Renin, N-terminal atrial natriuretic peptide (N-ANP), and ERK were activated while p38 MAPK was not. Treatment with AT1 receptor blockade prevented LVH and right ventricular hypertrophy, normalized systolic and diastolic dP/dt, N-ANP levels, and reduced collagen apposition. Similarly, TYR reduced LVH, N-ANP levels, and collagen apposition. Myocardial ERK activation did not depend on AT1 receptor signaling as it was not affected by AT1 receptor blockade. TYR abolished myocardial ERK activity. Smad2 activation was inhibited by AT1 receptor blockade but was unaltered by TYR. Ang II induced LV remodeling and fibrosis are dependent on both ERK and Smad2 activation. This process is prevented by both AT1 receptor blockade and TYR, and therefore inhibition of either pathway is equally efficacious in restoring LV function and architecture.

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Abbreviations

Ang :

Angiotensin

ARB :

Angiotensin II type 1 receptor blocker

AT 1 :

Angiotensin II type 1

EGF-R :

Epidermal growth factor receptor

ERK :

Extracellular signal-regulated kinase

JNK :

c-Jun N-terminal kinase

LV :

Left ventricle

LVH :

Left ventricular hypertrophy

MAPK :

Mitogen-activated protein kinase

N-ANP :

N-terminal atrial natriuretic peptide

RV :

Right ventricle

SD :

Sprague-Dawley

TBS-T :

Tris-buffered saline plus Tween 20

TGF :

Transforming growth factor

TYR :

Tyrphostin A46

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Acknowledgements

We thank Astrazeneca (Zoetermeer, The Netherlands) for providing the candesartan. D.J.v.V. is supported by the Netherlands Heart Foundation (grant D97-019). Y.M.P. is supported by the Netherlands Organization for Scientific Research (VIDI grant 016.036.346) and the Netherlands Heart Foundation (grant D99-018).

Author information

Correspondence to Rudolf A. de Boer.

Additional information

R.A.D.B. and S.P. contributed equally to this work

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de Boer, R.A., Pokharel, S., Flesch, M. et al. Extracellular signal regulated kinase and SMAD signaling both mediate the angiotensin II driven progression towards overt heart failure in homozygous TGR(mRen2)27. J Mol Med 82, 678–687 (2004). https://doi.org/10.1007/s00109-004-0579-3

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Keywords

  • Angiotensin II
  • Signal transduction
  • Fibrosis
  • Transforming growth factors
  • Transgenic animals