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Losartan reduces mortality in a genetic model of heart failure
Sophie Günther1, Hideo A Baba, Steffen Hauptmann
1Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle, Germany. sophie.guenther@medizin.uni-halle.de
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.
Insights
Losartan treatment improved survival and reduced cardiac damage in mice overexpressing calsequestrin (CSQ), a model of heart failure. This suggests angiotensin II receptor blockade can mitigate CSQ-induced heart problems.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Altered calcium (Ca2+) homeostasis is a hallmark of heart failure.
- Transgenic mice overexpressing calsequestrin (CSQ) in the heart serve as a model for heart failure, exhibiting hypertrophy, fibrosis, and premature death.
- CSQ is the primary Ca2+ binding protein within the sarcoplasmic reticulum lumen.
Purpose of the Study:
- To investigate the potential of losartan, an angiotensin II receptor inhibitor, to attenuate the detrimental effects of CSQ overexpression in a mouse model of heart failure.
- To evaluate the impact of losartan on cardiac function, survival, and pathological changes in CSQ-overexpressing mice.
Main Methods:
- Transgenic (TG) mice with cardiac-specific CSQ overexpression and wild-type (WT) littermates were treated with losartan (5 mg/kg/day) or vehicle orally from 4 weeks of age for 1 or 4 months.
- Cardiac hypertrophy was assessed by relative heart weight, fibrosis by Sirius red staining, and cardiac function by hemodynamic measurements.
- Survival rates and mean lifespan were monitored in both treated and control groups.
Main Results:
- CSQ overexpression led to significant cardiac hypertrophy, fibrosis, impaired cardiac function, and premature death in TG mice compared to WT controls.
- Losartan treatment significantly reduced mortality in TG mice, increasing mean lifespan from 116 to 193 days.
- Losartan administration also decreased relative heart weight, reduced fibrosis, and improved hemodynamic parameters in TG mice, without altering CSQ levels.
Conclusions:
- The angiotensin II receptor (type 1) plays a significant role in the progression of heart failure induced by calsequestrin overexpression.
- Blockade of the angiotensin II receptor with losartan effectively attenuates cardiac pathology and improves survival in this heart failure model.
- These findings highlight a potential therapeutic strategy for heart failure associated with altered calcium handling and sarcoplasmic reticulum protein expression.
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