Erythropoietin alleviates post-resuscitation myocardial dysfunction in rats potentially through increasing the expression of angiotensin II receptor type 2 in myocardial tissues

Abstract

Activation of renin-angiotensin system (RAS) is one of the pathological mechanisms associated with myocardial ischemia-reperfusion injury following resuscitation. The present study aimed to determine whether erythropoietin (EPO) improves post-resuscitation myocardial dysfunction and how it affects the renin-angiotensin system. Sprague-Dawley rats were randomly divided into sham, vehicle, epinephrine (EP), EPO and EP + EPO groups. Excluding the sham group, all groups underwent cardiopulmonary resuscitation (CPR) 4 min after asphyxia-induced cardiac arrest (CA). EP and/or EPO was administrated by intravenous injection when CPR began. The results demonstrated that the vehicle group exhibited lower mean arterial pressure, left ventricular systolic pressure, maximal ascending rate of left ventricular pressure during left ventricular isovolumic contraction and maximal descending rate of left ventricular pressure during left ventricular isovolumic relaxation (+LVdP/dt max and -LVdP/dt max, respectively), and higher left ventricular end-diastolic pressure, compared with the sham group following return of spontaneous circulation (ROSC). Few significant differences were observed concerning the myocardial function between the vehicle and EP groups; however, compared with the vehicle group, EPO reversed myocardial function indices following ROSC, excluding-LVdP/dt max. Serum renin and angiotensin (Ang) II levels were measured by ELISA. The serum levels of renin and Ang II were significantly increased in the vehicle group compared with the sham group, which was also observed for the myocardial expression of renin and Ang II receptor type 1 (AT1R), as determined by reverse transcription-quantitative polymerase chain reaction and western blotting. EPO alone did not significantly reduce the high serum levels of renin and Ang II post-resuscitation, but changed the protein levels of renin and AT1R expression in myocardial tissues. However, EPO enhanced the myocardial expression of Ang II receptor type 2 (AT2R) following ROSC. In conclusion, the present study confirmed that CA resuscitation activated the renin-Ang II-AT1R signaling pathway, which may contribute to myocardial dysfunction in rats. The present study confirmed that EPO treatment is beneficial for protecting cardiac function post-resuscitation, and the roles of EPO in alleviating post-resuscitation myocardial dysfunction may potentially be associated with enhanced myocardial expression of AT2R.

Angiotensin (1-7) Alleviates Postresuscitation Myocardial Dysfunction by Suppressing Oxidative Stress Through the Phosphoinositide 3-Kinase, Protein Kinase B, and Endothelial Nitric Oxide Synthase Signaling Pathway

“…Studies have found that the expression of AT1R is significantly upregulated in the myocardial tissues of CA-CPR-ROSC rats and that the expression of AT2R is relatively increased, which is one of the mechanisms of myocardial dysfunction after ROSC. 13 In CA-CPR-ROSC rats, Ang (1-7) can upregulate MasR expression and improve cardiac function after resuscitation. 12 In the current study, we investigated the time-dependent alterations in ATR expression and found that the expression of AT2R, MasR, and especially AT1R increased gradually in the myocardial tissues of rats at 2, 4, and 6 hours after ROSC.…”

“…10,11 Previous studies have found that the greater the increase in Ang Ⅱ expression in a rat model of CA and the sera of patients with CA, the more severely cardiac function is impaired. 12,13 Moreover, research has revealed that knockout of the angiotensinconverting enzyme-2 gene in rats decreases the level of Ang (1)(2)(3)(4)(5)(6)(7), increases the level of Ang II, and aggravates myocardial infarction. 14 In vitro and in vivo experiments have shown that knockout of the Mas gene in mice decreases left ventricular filling pressure, LVdp/dtmax, cardiac output, and the cardiac index.…”

Age and genotype dependent erythropoietin protection in COVID-19

“…In addition, Ang II may exert immune system modulation[ 33 ] and/or direct anti plasmodium activity[ 34 ]. The subsequently increased local tissue EPO levels would thus bypass systemic EPO prothrombotic effects while possibly also conferring the demanded tissue protection[ 35 ] and mitigation against Plasmodium invasion[ 12 , 26 , 32 ]. Significantly higher age-related ACE activities in serum are found in newborns and premature infants as well as healthy children and teenagers than adults [ 36 ].…”