Cardioprotective effects of pharmacological blockade of the mitochondrial calcium uniporter on myocardial ischemia-reperfusion injury

Abstract

To evaluate whether the attenuation of mitochondrial Ca 2+ overload produced by pharmacological blockade of mitochondrial Ca 2+ uniporter (MCU) protects the myocardium against injuries caused by cardiac ischemia and reperfusion (CIR). Methods: CIR was induced in adult male Wistar rats (300-350 g) by occlusion of the left anterior descendent coronary artery (10 min), followed by reperfusion (120 min). Rats were treated with different doses of MCU blocker ruthenium red (RuR), administered 5 min before ischemia or reperfusion. Results: In untreated rats, the incidences of ventricular arrhythmias (VA), atrioventricular block (AVB) and the lethality (LET) induced by CIR were 85%, 79% and 70%, respectively. In rats treated with RuR before ischemia, the incidences of VA, AVB and LET were significantly reduced to 62%, 25% and 25%, respectively. In rats treated with RuR after ischemia, the incidences of VA, AVB and LET were significantly reduced to 50%, 25% and 25%, respectively. Conclusion: The significant reduction of the incidence of CIR-induced VA, AVB and LET produced by the treatment with RuR indicates that the attenuation of mitochondrial Ca 2+ overload produced by pharmacological blockade of MCU can protect the myocardium against injuries caused by CIR.

Mitochondrial and Sarcoplasmic Reticulum Interconnection in Cardiac Arrhythmia

“…In this regard, using mCU transgenic mice, two independent groups confirmed our findings of the mCU’s critical role in matching the metabolic output during the adrenergic response ( Kwong et al, 2015 ; Wu et al, 2015 ). Blocking the mCU with ruthenium red (RuR) or Ru 360 min before the induction of ischemia-reperfusion (I/R) injury prevents the appearance of ventricular arrhythmia in rat models ( Garcia-Rivas Gde et al, 2006 ; Menezes-Rodrigues et al, 2020 ). In contrast, other studies have reported that enhancing Ca 2+ fluxes between the SR and mitochondria using mitochondrial Ca 2+ uptake enhancers is beneficial in preventing the appearance of ventricular arrhythmia associated with RyR2 dysfunction ( Schweitzer et al, 2017 ).…”

Cardioprotection stimulated by resveratrol and grape products prevents lethal cardiac arrhythmias in an animal model of ischemia and reperfusion

“…Surgical procedures used for induction of CIR in rats were made in accordance with methodology previously described [17][18][19] . Rats were anesthetized with urethane (1.25 g/kg), and fixed in the supine position.…”

“…After of 10 min of cardiac ischemia, the tourniquet was removed to allow coronary recirculation for 75 min (cardiac reperfusion). The cardiac electrical activity in all groups studied was monitored by electrocardiogram (ECG) system using a method previously described [17][18][19] . ECG analysis was performed during 100 min of duration (stabilization for 15 min, cardiac ischemia for 10 min and cardiac reperfusion for 75 min).…”

“…The ECG was recorded using a biopotential amplifier by means of needle electrodes placed subcutaneously on the limbs. Successful surgical obstruction of the coronary artery was validated by ECG alterations (increase in R wave and ST segment) caused by cardiac ischemia [17][18][19] . The body temperature was maintained at 37.5 ºC with a heated operating platform and appropriate heating lamps and was evaluated routinely via a rectal thermometer.…”

“…The cardiac activity in rats submitted to CIR was evaluate by ECG in accordance with methodology previously described [17][18][19] . The ECG data were recorded using an acquisition system AqDados 7.02 (Lynx Tecnologia Ltda., Brazil), an acquisition system AqDados 7.02 (Lynx Tecnologia Ltda., Brazil), and analyzed using the software AqDAnalysis 7 (Lynx Tecnologia Ltda., Brazil).…”