Recombinant human angiotensin-converting enzyme 2 plays a protective role in mice with sepsis-induced cardiac dysfunction through multiple signaling pathways dependent on converting angiotensin II to angiotensin 1–7

Abstract

Background: Sepsis-induced cardiac dysfunction (SICD) is a common complication of sepsis and contributes to mortality and the complexity of management in patients with sepsis. Recombinant human angiotensin-converting enzyme 2 (rhACE2) has been reported to protect the heart from injury and dysfunction in conditions which involve increased angiotensin II (Ang II). In this study, we aimed to detect the effects of rhACE2 on SICD.Methods: A SICD model was developed in male C57/B6 mice by lipopolysaccharide (LPS) intraperitoneal injection. When cardiac dysfunction was confirmed by echocardiography 3 hours after LPS administration, mice were treated with either saline, rhACE2, or rhACE2 + A779. All mice received echocardiographic examination at 6 hours after LPS injection and then were sacrificed for serum and myocardial tissues collection. Angiotensin, cardiac troponin I (cTnI), and inflammatory markers in serum were measured.Histopathology features were examined by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) staining to evaluate structure injury and cell pyroptosis rate in heart tissue respectively. Pyroptosis-related proteins and signaling pathways involved in nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in heart tissue were investigated by western blot (WB).Results: RhACE2 relieved myocardial injury and improved cardiac function in mice with SICD accompanied by decrease of Ang II and increase of angiotensin 1-7 (Ang 1-7) in serum. RhACE2 diminished activation of NLRP3 inflammasome, inflammatory response, and cell pyroptosis induced by LPS. In addition, rhACE2 partly inhibited activation of nuclear factor κB (NF-κB), the p38 mitogenactivated protein kinase (MAPK) pathway, and promoted activation of the AMP-activated protein kinase-α1 (AMPK-α1) pathway in heart tissue. Administration of A779 offset the inhibitive effects of rhACE2 on NLRP3 expression and protective role on cardiac injury and dysfunction in mice with SICD.Conclusions: RhACE2 plays a protective role in SICD, ameliorating cardiac injury and dysfunction through NF-κB, p38 MAPK, and the AMPK-α1/NLRP3 inflammasome pathway dependent on converting Ang II to Ang 1-7.

Effect of early stepwise cardiopulmonary rehabilitation on function and quality of life in sepsis patients

“…In the early stage of sepsis, under the action of various pathogenic factors, a large number of inflammatory cells can be activated, leading to the interaction of the proinflammatory response and anti-inflammatory response, causing increased capillary permeability, which results in generalized edema and a large amount of pleural and abdominal effusion[ 17 - 19 ]. Persistent generalized edema and large pleural effusions can cause hypotension, hypoxemia, and microcirculation disorders, and sustained hypoperfusion of systemic organs can cause organ dysfunction and ultimately respiratory and circulatory failure[ 20 - 22 ].…”

Myeloid ACE2 protects against septic hypotension and vascular dysfunction through Ang-(1–7)-Mas-mediated macrophage polarization

“…Moreover, a study suggested that exogenous supplementation with Ang (1–7) greatly ameliorates LPS-stimulated cardiac inflammation, apoptosis and dysfunction in mice [ 10 ]. More recently, administration of recombinant human ACE2 (rhACE2) to mice greatly attenuates LPS-stimulated activation of the NLRP3 inflammasome, NF-κB and p38 MAPK signals, inflammation, and increased Ang II and decreased Ang (1–7), which then protected against LPS-stimulated cardiac pyroptosis and dysfunction [ 50 ]. However, the significance of ACE2 in sepsis-induced hypotension and vascular dysfunction remains unclear.…”