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Chronic CaMKII inhibition reverses cardiac function and cardiac reserve in HF mice
Qianwen He1, Jun Cheng2, Yanggan Wang2
1Department of Anesthesiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Insights
Acute inhibition of CaMKII improves systolic function but worsens diastolic function in heart failure (HF) mice. Chronic inhibition improves both systolic and diastolic function, enhancing cardiac reserve without impairment.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Heart failure (HF) is a complex syndrome characterized by impaired cardiac function.
- Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a critical role in cardiac pathophysiology.
- Targeting CaMKII is a potential therapeutic strategy for HF.
Purpose of the Study:
- To investigate the impact of KN93, a CaMKII inhibitor, on cardiac function and reserve in a mouse model of HF.
- To differentiate the effects of acute versus chronic CaMKII inhibition.
Main Methods:
- Pressure-overload heart failure was induced in mice using transverse aortic constriction (TAC).
- Acute inhibition (AI) involved a single injection of KN93 or its inactive analogue KN92.
- Chronic inhibition (CI) involved daily injections of KN93, KN92, or saline for one week.
- Cardiac function was assessed using echocardiography and pressure-volume catheterization, with and without isoproterenol stimulation.
Main Results:
- Acute KN93 administration improved systolic parameters (EF, FS, dP/dtmax-EDV) but worsened diastolic function (-dP/dtmin, Tau).
- Chronic KN93 treatment enhanced both systolic (EF, FS, ESPVR) and diastolic function (no change in -dP/dtmin, Tau) and improved cardiac reserve.
- Chronic inhibition reversed the effects of isoproterenol stimulation in HF mice.
Conclusions:
- Acute CaMKII inhibition offers transient systolic benefits but impairs diastolic function in HF.
- Chronic CaMKII inhibition demonstrates therapeutic potential by improving both systolic and diastolic function and enhancing cardiac reserve in HF mice.
- CaMKII inhibition represents a promising therapeutic target for managing heart failure, with chronic administration showing superior benefits.
Aims:
The present study was to explore the impact of KN93 - a specific inhibitor of CaMKII - on cardiac function and cardiac reserve in HF mice.
Main Methods:
We have generated pressure-overload HF mice using modified transverse aortic constriction (TAC) method. For acute inhibition (AI) experiment, HF mice were randomly divided into HF group, HF + KN93 AI group and HF + KN92 AI group, using sham mice as control. Mice in HF + KN93 AI group and HF + KN92 AI group were injected with CaMKII inhibitor KN93 or its inactive analogue KN92 on post-TAC day 15, while mice in HF group and Sham group were treated with saline. For chronic inhibition (CI) experiment, mice were injected daily with KN93, KN92 or saline for one week. At baseline and after isoproterenol (Iso) injection, in vivo cardiac function was assessed by echocardiography and left ventricular pressure-volume catheter.
Key Findings:
Acute inhibition of CaMKII leads to decreased -dP/dtmin, increased EF, FS, longitudinal strain, longitudinal strain rate, ESPVR, dP/dtmax-EDV, PRSW, Tau and EDPVR, and unaltered reactivity to Iso in HF mice. Chronic inhibition results in increased EF, FS, longitudinal strain, longitudinal strain rate, ESPVR, dP/dtmax-EDV and PRSW, without alteration in -dP/dtmin, Tau and EDPVR. In addition, chronic inhibition reverses the effect of Iso on HF mice.
Significance:
Although acute CaMKII inhibition can repair systolic function in HF mice, it also exacerbates the diastolic function, whereas chronic inhibition improves both systolic function and cardiac reserve to β-adrenergic stimulation without impairing diastolic function.
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