ACE2 gene transfer ameliorates vasoreparative dysfunction in CD34+ cells derived from diabetic older adults

Abstract

Diabetes increases the risk for ischemic vascular diseases, which is further elevated in older adults. Bone marrow-derived hematopoietic CD34+ stem/progenitor cells have the potential of revascularization; however, diabetes attenuates vasoreparative functions. Angiotensin-converting enzyme 2 (ACE2) is the vasoprotective enzyme of renin–angiotensin system in contrast with the canonical angiotensin-converting enzyme (ACE). The present study tested the hypothesis that diabetic dysfunction is associated with ACE2/ACE imbalance in hematopoietic stem/progenitor cells (HSPCs) and that increasing ACE2 expression would restore reparative functions. Blood samples from male and female diabetic (n=71) or nondiabetic (n=62) individuals were obtained and CD34+ cells were enumerated by flow cytometry. ACE and ACE2 enzyme activities were determined in cell lysates. Lentiviral (LV) approach was used to increase the expression of soluble ACE2 protein. Cells from diabetic older adults (DB) or nondiabetic individuals (Control) were evaluated for their ability to stimulate revascularization in a mouse model of hindlimb ischemia (HLI). DB cells attenuated the recovery of blood flow to ischemic areas in nondiabetic mice compared with that observed with Control cells. Administration of DB cells modified with LV-ACE2 resulted in complete restoration of blood flow. HLI in diabetic mice resulted in poor recovery with amputations, which was not reversed by either Control or DB cells. LV-ACE2 modification of Control or DB cells resulted in blood flow recovery in diabetic mice. In vitro treatment with Ang-(1-7) modified paracrine profile in diabetic CD34+ cells. The present study suggests that vasoreparative dysfunction in CD34+ cells from diabetic older adults is associated with ACE2/ACE imbalance and that increased ACE2 expression enhances the revascularization potential.

An Investigation of the Inflammatory Landscape in the Brain and Bone Marrow of the APP/PS1 Mouse

“…Myelopoietic bias with aging or diabetes at the expense of leukocytosis or erythropoiesis was reported previously [78,79]. Both of these conditions are associated with decreased number of circulating vasculogenic progenitor cells [80,81]. APP/PS1 mice showed impaired glucose tolerance, hyperinsulinemia and hypercholesterolemia without increased HDL to oral sucrose [82].…”

Mitigation of Multi-Organ Radiation Injury with ACE2 Agonist Diminazene Aceturate

“…Additionally, agonism of Ang (1-7) signaling has also been observed to increase circulating hematopoietic progenitor cell populations (39,50). Moreover, in diabetic patients the loss of vasoreparative function has been linked to decreased ACE2 expression in CD34þ hematopoietic progenitors as lentiviral-mediated ACE2 gene transfer in CD34þ cells derived from diabetic patients rescued vasoreparative function in hind-limb ischemia models (29). Together these studies suggest DIZE may promote multi-organ recovery via activation of hematopoietic progenitors with vasoreparative function.…”

“…Prior studies have suggested agonism of ACE2/Ang (1-7) signaling promotes mobilization of bone marrow progenitors with vasoreparative function (19,29). Here, we evaluated whether a single subcutaneous injection of 15 mg/kg DIZE in non-irradiated rats induces bone marrow mobilization at 6 h. Data were compared to mobilization with a single dose of 0.55 mg/kg pegylated-G-CSF (Neulasta).…”

The role of telomerase reverse transcriptase in the mitochondrial protective functions of Angiotensin-(1–7) in diabetic CD34+ cells

“…[ 42 – 44 ] The protective effects were largely attributed to decreased oxidative stress, increased NO bioavailability, cell survival and proliferation by Akt-dependent pathway and reversal of paracrine dysfunction. [ 42 , 43 ] Ang-(1–7) reversed paracrine pro-inflammatory switch induced by diabetes, which included reversal of transforming growth factor- β1 (TGFβ1) upregulation. [ 38 , 43 ] In cancer cells, TGFβ1 was shown to regulate FL-TERT expression by inducing alternative splicing of TERT.…”

“…[ 42 , 43 ] Ang-(1–7) reversed paracrine pro-inflammatory switch induced by diabetes, which included reversal of transforming growth factor- β1 (TGFβ1) upregulation. [ 38 , 43 ] In cancer cells, TGFβ1 was shown to regulate FL-TERT expression by inducing alternative splicing of TERT. [ 45 ] Interestingly, TGFβ1-silencing also showed similar protective functions as that of Ang-(1–7) by restoring NO generation, proliferation and migration to areas of ischemic injury.…”