Apolipoprotein A-I mimetic peptide 4F attenuates kidney injury, heart injury, and endothelial dysfunction in sepsis

Abstract

Kidney injury, heart injury, and cytokine-induced vascular hyperpermeability are associated with high rates of morbidity and mortality in sepsis. Although the mechanism remains unknown, apolipoprotein A-I (apoA-I) mimetic peptide 4F reduces inflammation and protects HDL levels, which are reduced in sepsis. We hypothesized that 4F also protects kidneys and hearts in a rat model of cecal ligation and puncture (CLP). We divided Wistar rats into groups: sham-operated (control), CLP, and CLP+4F (10 mg/kg body wt ip, 6 h after CLP). At 24 h post-CLP, we evaluated cardiac function, mean arterial pressure (MAP), heart rate (HR), baroreflex sensitivity, total cholesterol, LDL, HDL, serum cytokines, and inulin clearance. We performed immunoblotting for protein regulators of vascular permeability (Slit2 and Robo4) and endothelial nitric oxide synthase (eNOS) in kidney tissue. We evaluated heart mitochondria with electron microscopy. Although there was no difference in MAP, the HR was significantly higher in CLP rats than in control and CLP+4F rats. In CLP+4F rats, baroreflex sensitivity and cardiac function were completely protected from the effects of CLP, as was glomerular filtration; heart mitochondria morphology was improved; sepsis-induced changes in serum cholesterol, LDL, HDL, and apoA-I were less common; all cytokines were lower than in CLP rats; and expression of Slit2, Robo4, and eNOS was completely restored. Administration of 4F inhibits inflammatory responses and strengthens the vascular barrier, protecting kidneys and hearts in an HDL-dependent manner. To determine the extent of the protective effect of 4F, further studies are needed.

Raised Plasma Robo4 and Cardiac Surgery-Associated Acute Kidney Injury

“…Robo4 interaction with its ligand Slit2 also prevented pathological angiogenesis in virus-induced keratitis [24]; HIV-induced lymphatic hyper-permeability [25]; changes in retinal endothelial permeability [26]; Andes virus-induced permeability increases in lung microvascular endothelial cells [27]; and inhibition of LPS-induced cytokine/chemokine release and ICAM-1 expression in HUVEC [28]. Also, a novel anti-inflammatory strategy (apoA-I mimetic 4F) that increased Robo4/Slit2 expression strengthened vascular barrier function, protecting kidneys and heart in an animal model of sepsis [29].…”

High-density lipoprotein mimetics: promises and challenges

“…Multiple mechanisms were suggested: ( i ) inhibition of VCAM expression [41, 47, 61, 62], ( ii ) reduction of cytokine expression [12, 61–63]; ( iii ) suppression of chemotaxis [64]; ( iv ) reduction of pro-inflammatory properties of modified LDL [65]; ( v ) inhibition of proinflammatory gene expression through altering the assembly of TLR–ligand complexes in cell membranes [66]. Which of these pathways is central to the anti-inflammatory ability of mimetic peptides is currently not known but is an active area of investigation.…”

“…ApoA-I and apoE mimetic peptides were shown to reduce amyloid burden in animal and cellular models of Alzheimer’s disease [9, 10]. In context of infectious diseases, apoA-I mimetic peptides reduced inflammation caused by an infection [11] and provided considerable multiple organ protection in sepsis [12]. Anti-inflammatory and anti-oxidation properties of HDL were behind the ability of apoA-I mimetics to reduce rejection after heart transplantation [13], alleviate asthma [14] and treat experimental arthritis [15].…”

Preliminary in vitro analysis of mechanism of cardiac microvascular endothelial barrier function

“…During heart failure, which is the final stage of various cardiovascular diseases, various types of abnormal microvascular structures can be observed, which may be associated with different cardiac microvascular characteristics (Moreira et al, 2014;Noyes et al, 2014). Endothelial cells (ECs) function as a semipermeable barrier between blood and interstitial tissues, thereby having antithrombotic and regulatory effects on endocrine function and angiostasis.…”

“…Vascular endothelial cadherin (VE-cadherin) is a vascular EC-specific cadherin that plays a crucial role in maintaining physiological functions of vascular ECs (Moreira et al, 2014). ADP-ribosylation factor 6 (Arf6) is a small GTP-binding protein belonging to the Ras superfamily.…”