Inhibition of Rac1 reduces store overload‐induced calcium release and protects against ventricular arrhythmia

Q: What are the key findings of this study?

Pharmacological or genetic inhibition of Rac1 significantly reduced the incidence of ventricular tachycardia during myocardial ischemia and reperfusion from 50% to 0% (p=0.0025).

Q: What is the clinical evidence from this study?

Population: Myocardial ischemia and reperfusion (I/R) (n=30). Intervention: Rac1 inhibition (Genetic knockdown or NSC23766) vs. Saline or wild-type control (Rac1 f/f). Primary outcome: Ventricular tachycardia incidence during reperfusion (p=0.0025).

Q: What does this research mean for the field?

Pharmacological or genetic inhibition of Rac1 significantly suppresses store overload-induced calcium release and protects against ventricular arrhythmias during myocardial ischemia and reperfusion. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

Lili Zhang; Xiangru Lu; Le Gui; Yan Wu; Stephen M. Sims; Guoping Wang; Qingping Feng

doi:10.1111/jcmm.12840

May 25, 2016Journal of Cellular and Molecular MedicineOpen Access

Inhibition of Rac1 reduces store overload‐induced calcium release and protects against ventricular arrhythmia

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Key result

Rac1 inhibition reduces reperfusion VT by an absolute ~50%.

P=0.0025
n=30

Why the study?

Does Rac1 inhibition reduce ventricular arrhythmia and store overload-induced calcium release during myocardial ischemia and reperfusion in a mouse model?

Key Points

To investigate whether genetic or pharmacological inhibition of the small GTPase Rac1 suppresses store overload-induced calcium release (SOICR) and protects against ventricular arrhythmias induced by myocardial ischaemia and reperfusion.
Adult control (Rac1(f/f)), cardiac-specific knockdown (Rac1(ckd)), and NSC23766-treated Rac1(f/f) mice were subjected to 45 min of myocardial ischaemia followed by 1 hr of reperfusion with continuous lead I ECG monitoring.
Isolated adult cardiomyocytes loaded with Fura-2AM were challenged with elevated extracellular calcium (up to 6 mM) and caffeine (10 mM) to assess SOICR, calcium transients, and sarcoplasmic reticulum calcium content.
Myocardial reactive oxygen species (ROS) production, ryanodine receptor 2 (RyR2) oxidation, and Rac1-GTP activity were assessed via DHE staining and Western blotting.
During reperfusion, the incidence of ventricular tachycardia was 5/10 in Rac1(f/f) mice versus 0/7 in NSC23766-treated mice and 0/13 in Rac1(ckd) mice (P = 0.0025); premature ventricular beats decreased from 100.2 ± 48.3 to 6.3 ± 3.3 and 5.4 ± 2.9, respectively (P = 0.0351).
In response to 6 mM external calcium, SOICR occurrence was >50% in Rac1(f/f) cardiomyocytes but decreased to 20–30% in Rac1(ckd) and NSC23766-treated cells (P < 0.01), with the SOICR calcium threshold doubling from ~3 mM to 6 mM.
Rac1 knockdown significantly inhibited ischaemia/reperfusion-induced myocardial ROS production and RyR2 oxidation without altering infarct size.

Structured PICO

Does Rac1 inhibition reduce ventricular arrhythmia and store overload-induced calcium release during myocardial ischemia and reperfusion in a mouse model?

P

Population

30 adult male mice subjected to myocardial ischemia and reperfusion to evaluate the effect of Rac1 inhibition on ventricular arrhythmias.

I

Intervention

Rac1 inhibition via cardiac-specific genetic knockdown (Rac1 ckd) or pharmacological inhibitor NSC23766 (2.5 mg/kg IP administered 30 min before I/R).

C

Comparator

Control wild-type mice (Rac1 f/f) treated with saline.

O

Outcome

Incidence of ventricular tachycardia (VT) and number of premature ventricular contractions (PVC) during ischemia and reperfusion.surrogate

Main Result

Absolute Event Rate: 0% vs 50%

Absolute Risk Reduction: 50%

p-value: p=0.0025

Rac1 inhibition suppresses store overload-induced calcium release and prevents ventricular arrhythmias during ischemia-reperfusion, identifying a potential novel anti-arrhythmic mechanism.

Limitations

Limited to addressing the role of Rac1 in RyR2-mediated cardiac Ca2+ handling without examining effects on other key players like Na+/Ca2+ exchanger, SERCA, and L-type Ca2+ channels.
Limited to addressing the role of Rac1 in RyR2-mediated cardiac Ca2+ handling; did not examine effects on Na+/Ca2+ exchanger, SERCA, and L-type Ca2+ channels.

Implication

Rac1 inhibition should not yet inform clinical arrhythmia management; hypothesis-generating for translation in ischemia-reperfusion models.

Abstract

Rac1 is a small GTPase and plays key roles in multiple cellular processes including the production of reactive oxygen species (ROS). However, whether Rac1 activation during myocardial ischaemia and reperfusion (I/R) contributes to arrhythmogenesis is not fully understood. We aimed to study the effects of Rac1 inhibition on store overload-induced Ca(2+) release (SOICR) and ventricular arrhythmia during myocardial I/R. Adult Rac1(f/f) and cardiac-specific Rac1 knockdown (Rac1(ckd) ) mice were subjected to myocardial I/R and their electrocardiograms (ECGs) were monitored for ventricular arrhythmia. Myocardial Rac1 activity was increased and ventricular arrhythmia was induced during I/R in Rac1(f/f) mice. Remarkably, I/R-induced ventricular arrhythmia was significantly decreased in Rac1(ckd) compared to Rac1(f/f) mice. Furthermore, treatment with Rac1 inhibitor NSC23766 decreased I/R-induced ventricular arrhythmia. Ca(2+) imaging analysis showed that in response to a 6 mM external Ca(2+) concentration challenge, SOICR was induced with characteristic spontaneous intracellular Ca(2+) waves in Rac1(f/f) cardiomyocytes. Notably, SOICR was diminished by pharmacological and genetic inhibition of Rac1 in adult cardiomyocytes. Moreover, I/R-induced ROS production and ryanodine receptor 2 (RyR2) oxidation were significantly inhibited in the myocardium of Rac1(ckd) mice. We conclude that Rac1 activation induces ventricular arrhythmia during myocardial I/R. Inhibition of Rac1 suppresses SOICR and protects against ventricular arrhythmia. Blockade of Rac1 activation may represent a new paradigm for the treatment of cardiac arrhythmia in ischaemic heart disease.

Discussion

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Cite This Study

Zhang et al. (2016) studied Myocardial ischemia and reperfusion (I/R) (n=30). Rac1 inhibition (Genetic knockdown or NSC23766) vs. Saline or wild-type control (Rac1 f/f) was evaluated on Ventricular tachycardia incidence during reperfusion (p=0.0025). Pharmacological or genetic inhibition of Rac1 significantly reduced the incidence of ventricular tachycardia during myocardial ischemia and reperfusion from 50% to 0% (p=0.0025).

synapsesocial.com/papers/6a6008a93df69035db7c4ab1 https://doi.org/10.1111/jcmm.12840

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Inhibition of Rac1 reduces store overload‐induced calcium release and protects against ventricular arrhythmia

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Inhibition of Rac1 reduces store overload‐induced calcium release and protects against ventricular arrhythmia

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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