Losartan reduces mortality in a genetic model of heart failure

Sophie Günther, Hideo A. Baba, Steffen Hauptmann, Hans Jürgen Holzhausen, Claudia Großmann, Karla Punkt, Tina Kusche, Larry R. Jones, Ulrich Gergs, Joachim Neumann

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7 Scopus citations


Altered Ca2+ homoeostasis accompanies heart failure. As a model of heart failure, transgenic mice (TG) with selective overexpression of calsequestrin (CSQ) in the heart were used. CSQ is the main Ca2+ binding protein in the lumen of the junctional sarcoplasmic reticulum. Overexpression of CSQ leads to hypertrophy, fibrosis, heart failure, cardiac arrhythmias, and ultimately premature death compared to littermate controls (WT). In the present study, cardiac hypertrophy was noted at 2 months of age (relative heart weight 6.4 ± 0.2 mg/g in WT and 11.2 ± 0.3 mg/g in TG, n = 7, p < 0.05) which progressed at 5 months of age (relative heart weight 15.5 ± 1.1 mg/g in TG, n = 11). Furthermore, an increased degree of fibrosis (from 0.29 ± 0.04 in WT to 0.77 ± 0.06 in TG, n = 8, p < 0.05) was quantified by sirius red staining. Cardiac function was greatly impaired in TG as exemplified by reduced pressure development and cardiac arrhythmias. It is hypothesized that losartan, an inhibitor of angiotensin II receptors, might be able to attenuate these detrimental effects. Hence, TG and WT were treated for 1 or 4 months perorally with losartan (5 mg/kg/day) or solvent alone (control conditions) starting at 4 weeks of age. Under control conditions, none of the WT died within the observation period whereas all TG died within 9 months. Losartan treatment reduced the mortality of TG: Mean life span was raised from 116 to 193 days (n = 18 end, p < 0.05). Likewise, losartan reduced relative heart weight and the degree of fibrosis. In addition, losartan improved hemodynamic parameters, like left ventricular pressure and its first derivative. However, losartan treatment did not modify overexpression of CSQ in the heart of TG. These results imply that the angiotensin II receptor (type 1) contributes to heart failure due to CSQ overexpression, as its blockade improved survival.

Original languageEnglish (US)
Pages (from-to)265-278
Number of pages14
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Issue number3
StatePublished - Sep 1 2010


  • CSQ mice
  • Heart failure
  • Losartan

ASJC Scopus subject areas

  • Pharmacology

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    Günther, S., Baba, H. A., Hauptmann, S., Holzhausen, H. J., Großmann, C., Punkt, K., Kusche, T., Jones, L. R., Gergs, U., & Neumann, J. (2010). Losartan reduces mortality in a genetic model of heart failure. Naunyn-Schmiedeberg's Archives of Pharmacology, 382(3), 265-278. https://doi.org/10.1007/s00210-010-0544-3