Losartan reduces mortality in a genetic model of heart failure.

Abstract

Altered Ca(2+) 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 Ca(2+) 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.

• Authors: Sophie Günther, Hideo A Baba, Steffen Hauptmann, Hans-Jürgen Holzhausen, Claudia Grossmann, Karla Punkt, Tina Kusche, Larry R Jones, Ulrich Gergs, Joachim Neumann
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 382 Issue 3 Pg. 265-78 (Sep 2010) ISSN: 1432-1912 [Electronic] Germany
• PMID: 20697885 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Agtrap protein, mouse
• Angiotensin II Type 1 Receptor Blockers
• Calsequestrin
• Losartan

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Calsequestrin (metabolism)
• Disease Models, Animal
• Female
• Fibrosis
• Heart Failure (drug therapy, mortality, physiopathology)
• Hemodynamics (drug effects)
• Losartan (pharmacology)
• Male
• Mice
• Mice, Transgenic
• Organ Size
• Time Factors