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Chymase inhibition reduces the progression to heart failure after autoimmune myocarditis in rats
Suresh S Palaniyandi1, Yusuke Nagai, Kenichi Watanabe
1Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata City, 956-8603, Japan.
Insights
Inhibiting chymase improved heart function and reduced fibrosis in rats with dilated cardiomyopathy. This suggests chymase inhibition is a potential treatment for heart failure by preventing pathological remodeling and inflammation.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Biochemistry
Background:
- Chymase is recognized as a key enzyme in angiotensin II generation within the cardiovascular system.
- Emerging research indicates chymase possesses diverse functions beyond its known enzymatic activity.
- Dilated cardiomyopathy pathophysiology involves complex mechanisms, including inflammation and cardiac remodeling.
Purpose of the Study:
- To investigate the therapeutic potential of chymase inhibition in a rat model of postmyocarditis dilated cardiomyopathy.
- To elucidate the mechanism of action of chymase inhibition in mitigating cardiac disease progression, particularly in rats where chymase does not produce angiotensin II.
- To evaluate the dose-dependent effects of a novel chymase inhibitor, TY-51469.
Main Methods:
- Utilized a rat model of postmyocarditis dilated cardiomyopathy induced by myosin immunization.
- Administered the novel chymase inhibitor TY-51469 at two different doses (0.1 mg/kg/day and 1 mg/kg/day) or vehicle control for 4 weeks.
- Assessed cardiac function, myocardial fibrosis, fibrogenesis, transforming growth factor-beta1 (TGF-beta1), collagen III, hypertrophy (indicated by atrial natriuretic peptide - ANP), mast cell activity, aldosterone synthase levels, and survival rates.
Main Results:
- Chymase inhibitor treatment dose-dependently improved survival rates and myocardial function in postmyocarditis rats.
- Significant reductions were observed in myocardial fibrosis, fibrogenesis, hypertrophy, mast cell activity, TGF-beta1, collagen III, and ANP levels.
- Treatment with the chymase inhibitor also led to decreased myocardial aldosterone synthase levels.
Conclusions:
- Inhibition of chymase effectively reduces the pathogenesis of postmyocarditis dilated cardiomyopathy in rats.
- Chymase inhibition mitigates cardiac disease progression by preventing pathological remodeling and residual inflammation.
- TY-51469 demonstrates therapeutic potential for treating dilated cardiomyopathy and preventing heart failure progression.
Abstract:
Chymase has been known as a local angiotensin II-generating enzyme in the cardiovascular system in dogs, monkeys, hamsters, and humans; however, recently it was reported that chymase also has various other functions. Therefore, we decided to examine whether the inhibition of chymase improves disease conditions associated with the pathophysiology of dilated cardiomyopathy in rats and its possible mechanism of action as rat chymase is unable to produce angiotensin II. We examined the effect of TY-51469, a novel chymase inhibitor (0.1 mg/kg/day [group CYI-0.1, n = 15] and 1 mg/kg/day [group CYI-1, n = 15]), in myosin-immunized postmyocarditis rats. Another group of myosin-immunized rats was treated with vehicle (group V, n = 15). Age-matched normal rats without immunization (group N, n = 10) were also included in the study. After 4 weeks of treatment, we evaluated cardiac function; area of fibrosis; fibrogenesis; levels of transforming growth factor (TGF)-beta1 and collagen III; hypertrophy and its marker, atrial natriuretic peptide (ANP); and mast cell activity. Survival rate and myocardial functions improved dose-dependently with chymase inhibitor treatment after myosin immunization. A reduction in the percent area of myocardial fibrosis, fibrogenesis, myocardial hypertrophy, and mast cell activity along with a reduction in TGF-beta1, collagen III, and ANP levels in the myocardium were noted in postmyocarditis rats that received chymase inhibitor treatment. The treatment also decreased myocardial aldosterone synthase levels in those animals. Inhibition of chymase reduces the pathogenesis of postmyocarditis dilated cardiomyopathy and progression to heart failure by preventing the pathological remodeling and residual inflammation in rats.
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