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 Jones, Ulrich Gergs, Joachim Neumann

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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
Pages (from-to)265-278
Number of pages14
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume382
Issue number3
DOIs
StatePublished - Sep 2010

Fingerprint

Losartan
Genetic Models
Transgenic Mice
Calsequestrin
Heart Failure
Mortality
Fibrosis
Weights and Measures
Cardiac Arrhythmias
Angiotensin Type 1 Receptor
Angiotensin Receptors
Premature Mortality
Cardiomegaly
Sarcoplasmic Reticulum
Ventricular Pressure
Hypertrophy
Carrier Proteins
Homeostasis
Hemodynamics
Observation

Keywords

  • CSQ mice
  • Heart failure
  • Losartan

ASJC Scopus subject areas

  • Pharmacology

Cite this

Günther, S., Baba, H. A., Hauptmann, S., Holzhausen, H. J., Großmann, C., Punkt, K., ... 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

Losartan reduces mortality in a genetic model of heart failure. / Günther, Sophie; Baba, Hideo A.; Hauptmann, Steffen; Holzhausen, Hans Jürgen; Großmann, Claudia; Punkt, Karla; Kusche, Tina; Jones, Larry; Gergs, Ulrich; Neumann, Joachim.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 382, No. 3, 09.2010, p. 265-278.

Research output: Contribution to journalArticle

Günther, S, Baba, HA, Hauptmann, S, Holzhausen, HJ, Großmann, C, Punkt, K, Kusche, T, Jones, L, Gergs, U & Neumann, J 2010, 'Losartan reduces mortality in a genetic model of heart failure', Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 382, no. 3, pp. 265-278. https://doi.org/10.1007/s00210-010-0544-3
Günther S, Baba HA, Hauptmann S, Holzhausen HJ, Großmann C, Punkt K et al. Losartan reduces mortality in a genetic model of heart failure. Naunyn-Schmiedeberg's Archives of Pharmacology. 2010 Sep;382(3):265-278. https://doi.org/10.1007/s00210-010-0544-3
Günther, Sophie ; Baba, Hideo A. ; Hauptmann, Steffen ; Holzhausen, Hans Jürgen ; Großmann, Claudia ; Punkt, Karla ; Kusche, Tina ; Jones, Larry ; Gergs, Ulrich ; Neumann, Joachim. / Losartan reduces mortality in a genetic model of heart failure. In: Naunyn-Schmiedeberg's Archives of Pharmacology. 2010 ; Vol. 382, No. 3. pp. 265-278.
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