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Development of a novel murine heart failure model overexpressing human renin and angiotensinogen
Tomoya Hara1, Takeshi Yamamura1, Mirei Murakami-Asahina1
1Takeda Pharmaceutical Co Ltd Shonan Research Center, Fujisawa, Japan.
Abstract:
Renin is the rate-limiting enzyme of the renin-angiotensin system cascade, which drives the pathophysiological progression of heart failure. Species differences in the amino acid sequence of the catalytic domain of renin limit evaluations of the potency and efficacy of human renin inhibitors in animal models, and a high dose of inhibitors is usually needed to show its organ-protective effects in rodents. In the present study, we developed a novel murine heart failure model (triple-tg) to enable us to evaluate the cardioprotective effect of renin inhibitors at more relevant doses for humans, by cross-breeding calsequestrin transgenic (CSQ-tg) mice with human renin and human angiotensinogen double-transgenic mice. The triple-tg mice exhibited increased plasma renin activity, worsened cardiac hypertrophy, and higher mortality compared to CSQ-tg mice. Triple-tg mice treated with 10 mg·kg-1 of TAK-272 (imarikiren/SCO-272), an orally active direct renin inhibitor, exhibited improvements in heart failure phenotypes, such as cardiac hypertrophy and survival rate; however, a dose of 300 mg·kg-1 was required to improve symptoms in CSQ-tg mice. Our results suggest that this newly generated triple-tg heart failure model is useful to evaluate the cardioprotective effects of human renin inhibitors at clinically relevant doses, thereby minimizing the concerns of off-target effects related to much higher drug exposure than that achieved in clinical study.
Insights
A new mouse model for heart failure allows researchers to test human renin inhibitors at relevant doses. This model shows improved heart function and survival when treated with direct renin inhibitors.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Genetics
Background:
- Renin initiates the renin-angiotensin system, a key driver of heart failure.
- Species differences in renin hinder the evaluation of human renin inhibitors in animal models.
- High doses of inhibitors are often needed in rodents, limiting clinical relevance.
Purpose of the Study:
- To develop a novel murine heart failure model for evaluating human renin inhibitors.
- To enable testing of cardioprotective effects at clinically relevant doses.
- To overcome limitations of existing animal models due to species differences in renin.
Main Methods:
- Cross-breeding calsequestrin transgenic (CSQ-tg) mice with human renin and human angiotensinogen double-transgenic mice to create a triple-transgenic (triple-tg) model.
- Assessing cardiac hypertrophy, plasma renin activity, and mortality in triple-tg and CSQ-tg mice.
- Administering TAK-272 (imarikiren), an oral direct renin inhibitor, to evaluate dose-dependent effects on heart failure phenotypes.
Main Results:
- Triple-tg mice displayed increased plasma renin activity, exacerbated cardiac hypertrophy, and higher mortality compared to CSQ-tg mice.
- TAK-272 treatment (10 mg·kg⁻¹) improved heart failure phenotypes and survival in triple-tg mice.
- A significantly higher dose (300 mg·kg⁻¹) of TAK-272 was required to improve symptoms in CSQ-tg mice.
Conclusions:
- The novel triple-tg mouse model is effective for evaluating cardioprotective effects of human renin inhibitors.
- This model allows assessment at doses relevant to human clinical studies.
- It minimizes concerns about off-target effects from excessively high drug exposure in preclinical testing.
