Targeting of Extracellular RNA Reduces Edema Formation and Infarct Size and Improves Survival After Myocardial Infarction in Mice

Abstract

BackgroundFollowing myocardial infarction (MI), peri‐infarct myocardial edema formation further impairs cardiac function. Extracellular RNA (eRNA) released from injured cells strongly increases vascular permeability. This study aimed to assess the role of eRNA in MI‐induced cardiac edema formation, infarct size, cardiac function, and survival after acute MI and to evaluate the therapeutic potential of ribonuclease 1 (RNase‐1) treatment as an eRNA‐degrading intervention.Methods and ResultsC57BL/6J mice were subjected to MI by permanent ligation of the left anterior descending coronary artery. Plasma eRNA levels were significantly increased compared with those in controls starting from 30 minutes after ligation. Systemic application of RNase‐1, but not DNase, significantly reduced myocardial edema formation 24 hours after ligation compared with controls. Consequently, eRNA degradation by RNase‐1 significantly improved the perfusion of collateral arteries in the border zone of the infarcted myocardium 24 hours after ligation of the left anterior descending coronary artery, as detected by micro–computed tomography imaging. Although there was no significant difference in the area at risk, the area of vital myocardium was markedly larger in mice treated with RNase‐1 compared with controls, as detected by Evans blue and 2,3,5‐triphenyltetrazolium chloride staining. The increase in viable myocardium was associated with significantly preserved left ventricular function, as assessed by echocardiography. Moreover, RNase‐1 significantly improved 8‐week survival following MI.ConclusionseRNA is an unrecognized permeability factor in vivo, associated with myocardial edema formation after acute MI. RNase‐1 counteracts eRNA‐induced edema formation and preserves perfusion of the infarction border zone, reducing infarct size and protecting cardiac function after MI.

Ribonuclease 1 attenuates septic cardiomyopathy and cardiac apoptosis in a murine model of polymicrobial sepsis

“…Most notably, treatment of septic mice with RNase 1 attenuated the rise in cardiac Bax levels, activation of caspase-9 and caspase-3, the decrease in Bcl-2 and TUNEL + cells caused by sepsis in the heart (Figure 6). In line with our findings, Stieger et al reported a reduction of apoptosis 24 hours after ligation of the left anterior descending artery (LAD) in mice treated with RNase 1 (37). Treatment with RNase 1 in sham-operated mice did not show any apoptosis induction ( Figure 6).…”

“…We confirm that the model of polymicrobial sepsis used here, indeed, results in a substantial cardiac dysfunction defined by a significant decrease in EF, FS, and fraction area change ( Figure 5). Stieger et al reported an increase of FS in mice treated with RNase 1 (50 μg/kg) compared with mice treated with saline 24 hours after myocardial infraction (37).We also detected a significant reduction in left ventricular cardiac dysfunction in CLP mice treated with RNase 1, as determined by a substantial increase in EF, FS, fraction area change, and cardiac output ( Figure 5). Moreover, we detected a significant reduction in the release of TNF in CLP mice treated with RNase 1 when compared with CLP mice treated with vehicle (Figure 7A).…”

“…This hypothesis is also confirmed by Stieger and colleagues, who reported increased eRNA levels within 30 minutes and maximal eRNA levels at 2 hours after ligation of the LAD. However, 4 hours after ligation of LAD, the eRNA levels had returned to baseline (37).…”

Anthocyanidin attenuates myocardial ischemia induced injury via inhibition of ROS‐JNK‐Bcl‐2 pathway: New mechanism of anthocyanidin action

“…After 1 week, LAD ligation was performed as described earlier (Y. Cao et al, ). Briefly, mice were fully anesthetized using ketamine and xylazine (80 and 10 mg/kg, respectively; Sigma‐Aldrich, St. Louis, MO) via intraperitoneal injection (0.1 ml/10 g of body weight; Stieger et al, ). An endotracheal tube connected to a rodent respirator (Harvard Rodent Ventilator, Harvard Apparatus, Holliston, MA, USA) was introduced into the trachea.…”

The Extraordinary Role of Extracellular RNA in Arteriogenesis, the Growth of Collateral Arteries

“…Other forms of extracellular RNA such as microRNA have also been suggested to have a regulatory effect on collateral remodeling during arteriogenesis through modulation of intracellular signaling pathways; however, whether this effect is positive or negative seems to depend on the specific microRNA [5][6][7][8]. In terms of cardiovascular disease, eRNA released upon cellular damage has proven to have adverse effects in, e.g., ischemia/reperfusion injury, transplantation or atherosclerosis by mediating vascular edema, thrombus formation and inflammation [9][10][11][12][13][14]. This review aims to further elucidate the beneficial role of eRNA during the various stages of arteriogenesis.…”