Inhibition of Pyk2 Improves Cx43 Intercalated Disc Localization, Infarct Size, and Cardiac Function in Rats With
Li Zheng1, Gaelle Spagnol1, Devashri R Gandhi2
1Department of Biochemistry and Molecular Biology (L.Z., G.S., P.L.S.), University of Nebraska Medical Center, Omaha.
Background:
Heart failure causes changes in Cx43 (Connexin43) regulation that are associated with arrhythmic heart disease. Pyk2 (proline-rich tyrosine kinase 2) is activated in cardiomyopathies and phosphorylates Cx43 to decrease intercellular communication. This study was designed to determine if Pyk2 inhibition improves cardiac function in a myocardial infarction (MI)-induced heart failure model in rats.
Methods:
MI (ligation of left anterior descending artery) rats were treated with the Pyk2 inhibitor PF4618433. Hemodynamic and structural parameters were monitored in Sham (n=5), MI-vehicle (n=5), and MI-PF4618433 (n=8) groups. Heart tissues were collected after 6 weeks to assess Pyk2 and Cx43 protein level and localization.
Results:
PF4618433 produced no observed adverse effects and inhibited ventricular Pyk2. PF4618433 reduced the MI infarct size from 34% to 17% (P=0.007). PF4618433 improved stroke volume (P=0.031) and cardiac output (P=0.009) in comparison to MI-vehicle with values similar to the Sham group. PF4618433 also led to an increase in the ejection fraction (P=0.002) and fractional shortening (P=0.006) when compared with the MI-vehicle (32% and 35% improvement, respectively) yet were lower in comparison with the Sham group. Pyk2 inhibition decreased Cx43 tyrosine phosphorylation (P=0.043) and maintained Cx43 at the intercalated disc in the distal ventricle 6 weeks post-MI.
Conclusions:
Unlike other attempts to decrease Cx43 remodeling after MI-induced heart failure, inhibition of Pyk2 activity maintained Cx43 at the intercalated disc. This may have aided in the reduced infarct size (acute time frame) and improved cardiac function (chronic time frame). Additionally, we provide evidence that Pyk2 is activated following MI in human left ventricle, implicating a novel potential target for therapy in patients with heart failure.
Insights
Inhibiting proline-rich tyrosine kinase 2 (Pyk2) improved cardiac function and reduced infarct size in a rat model of heart failure. This Pyk2 inhibition maintained Connexin43 (Cx43) localization, suggesting a new therapeutic target for heart failure.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Pharmacology
Background:
- Heart failure is associated with altered Connexin43 (Cx43) regulation, contributing to arrhythmias.
- Proline-rich tyrosine kinase 2 (Pyk2) activation in cardiomyopathies leads to Cx43 phosphorylation and reduced intercellular communication.
Purpose of the Study:
- To investigate whether Pyk2 inhibition can improve cardiac function in a rat model of myocardial infarction (MI)-induced heart failure.
Main Methods:
- Rats with MI were treated with the Pyk2 inhibitor PF4618433.
- Hemodynamic and structural parameters were monitored.
- Cardiac tissues were analyzed for Pyk2 and Cx43 levels and localization post-MI.
Main Results:
- PF4618433 inhibited ventricular Pyk2 and significantly reduced MI infarct size.
- The inhibitor improved stroke volume, cardiac output, ejection fraction, and fractional shortening compared to vehicle-treated MI rats.
- Pyk2 inhibition decreased Cx43 tyrosine phosphorylation and preserved Cx43 localization at the intercalated disc.
Conclusions:
- Pyk2 inhibition offers a novel therapeutic strategy for heart failure by maintaining Cx43 at the intercalated disc, improving cardiac function, and reducing infarct size.
- Pyk2 activation is observed in human hearts post-MI, highlighting its potential as a therapeutic target for heart failure patients.
