High-mobility group box 1 (HMGB1) triggers and amplifies inflammation cascade following ischemic injury and its elevated levels are associated with adverse clinical outcomes in patients with myocardial infarction (MI). expression of HMGB1 RAS components and inflammatory cytokines. ACE2 in the heart of the ACE2 KI mice was 58-fold higher than WT controls. ACE2-MI mice exhibited a remarkable preservation of cardiac Rosuvastatin function and reduction of infarct size in comparison to WT-MI mice. Notably ACE2 overexpression significantly reduced the MI-induced increase in apoptosis macrophage infiltration and HMGB1 and pro-inflammatory cytokine expression (TNF-α and IL-6). Moreover in an in vitro study ACE2 activation prevented the hypoxia-induced cell death and upregulation of HMGB1 in adult cardiomyocytes. This protective effect is correlated with downregulation of HMGB1 and downstream pro-inflammatory cascades which could be useful for Rosuvastatin the development of novel treatment for ischemic heart disease. promoter on one allele were generated by using technology. Briefly a gene cassette containing FLAG-tagged mouse ACE2 proceeded by a locus to generate deleter mice (β-actin-Cre or Alk1Cre) offspring of these cassette deleted namely the and wild-type littermate control mice which were maintained on a 129/B6 mixed background. Based on the generation technology these mice (ACE2 mice) have the ACE2 gene overexpressed all through the body. Myocardial infarction ACE2 transgenic mice and their littermate WT controls aged from 8 to 10 weeks were divided into Rabbit Polyclonal to Smad2 (phospho-Ser465). four experimental groups: (1) WT-Sham (test or one-way ANOVA with Bonferroni correction for multiple comparisons. Histology scores of myocardial injury severity were compared using the Mann–Whitney test between WT-MI and ACE2-MI groups. Values of <0.05 were considered statistically significant. All of the data were analyzed using GraphPad Prism Rosuvastatin 5 software (GraphPad Prism Institute Inc). Results Characterizations of ACE2 knock-in (KI) mice ACE and ACE2 mRNA levels in the heart lung liver kidney spleen and paraventricular nucleus (PVN) of the brain were quantified using real-time PCR. The PVN was selected due to its critical role in cardiovascular pathophysiology. ACE2 was significantly upregulated in the vital organs of ACE2 KI mice in comparison Rosuvastatin to WT controls (Table 1) with 5-fold 58 and 219-fold upregulation of ACE2 in the kidney heart and PVN respectively. Overexpression of ACE2 did not alter the endogenous ACE levels aside from a slight elevation of ACE in the PVN. ACE2/ACE ratio was highest in the liver followed by the brain and heart. Cardiac hemodynamics and mean arterial pressure of ACE2-KI were comparable to those of WT mice (Table 2). This observation was in contrast to a previous study of Donoghue et al. who reported abnormal blood pressure and conduction anomalies including heart block and ventricular tachycardia in ACE2 transgenic mice [25]. Table 1 ACE2 and ACE gene expression in vital organs of WT and ACE2 mice Table 2 Cardiac hemodynamics of WT and ACE2 KI mice following MI ACE2 overexpression attenuates MI-induced left ventricle dysfunction and associated cardiac remodeling Heart function for four groups of animals WT-Sham WT-MI ACE2-Sham and ACE2-MI mice were measured using echocardiography and Millar catheterization. WT-MI animals showed a 59 % decrease in ejection fraction (EF) 6 increase in left ventricular end-systolic volume (ESV) 1.7 in end-diastolic volume (EDV) 52 % elevation in left ventricular end-diastolic pressure (LVEDP) 59 % decrease in dP/dtmax and 39 % reduction in dP/dtmin as compared to WT-Sham (Table 2). ACE2 mice were protected from MI-induced damage Rosuvastatin with preserved heart function compared to WT-MI with less decrease in EF (21 % reduction for ACE2-MI vs. 59 % for WT-MI p<0.05). No significant differences were observed in mean arterial pressure (MAP) and heart rate (HR) between WT and ACE2 mice for both sham and MI groups. Consistent with the echocardiographic results (Table 2 and Fig. 1a) the WT-MI mice developed ventricular hypertrophy as measured by the VW/TL ratio which was not observed in the ACE2-MI mice (Fig. 1a). Additionally we examined the infarcted area in the MI animals using fibrosis staining and infarction size was quantified as the percentage of fibrotic area of the free wall of left.