Increased expression of Sonic hedgehog restores diabetic endothelial progenitor cells and improves cardiac repair after acute myocardial infarction in diabetic mice

Abstract

Damaged endothelial progenitor cells (EPCs) are associated with poor prognosis in diabetic myocardial infarction (DMI). Our previous studies revealed that an impaired Sonic hedgehog (Shh) pathway contributes to insufficient function in diabetic EPCs; however, the roles of the Shh pathway in diabetic EPC apoptosis under basal and hypoxic/ischemic conditions remain unknown. Therefore, the present study investigated whether Shh revitalized diabetic EPCs and consequently improved the deteriorative status of DMI. For this purpose, streptozotocin injection was used in male C57/BL6 mice to induce type-1 diabetes, and diabetic EPCs were isolated from the bone marrow. Apoptosis, cell function, and protein expression were investigated in EPCs in vitro . Mouse hearts were injected with adenovirus Shh-modified diabetic EPCs (DM-EPC Shh ) or control DM-EPC Null immediately after coronary artery ligation in vivo . Cardiac function, capillary numbers, fibrosis, and cell apoptosis were then detected. First, the in vitro results demonstrated that the apoptosis of diabetic EPCs was reduced following treatment with Shh protein for 24 h, under normal or hypoxic conditions. BMI1 proto-oncogene (Bmi1), an antiapoptotic protein found in several cells, was reduced in diabetic EPCs under normal or hypoxic conditions, but was upregulated after Shh protein stimulation. When Bmi1-siRNA was administered, the antiapoptotic effect of Shh protein was significantly reversed. In addition, p53, a Bmi1-targeted gene, was demonstrated to mediate the antiapoptotic effect of the Shh/Bmi1 pathway in diabetic EPCs. The Shh/Bmi1/p53 axis also enhanced the diabetic EPC function. In vivo , Shh-modified diabetic EPCs exhibited increased EPC retention and decreased apoptosis at 3 days post-DMI. At 14 days post-DMI, these cells presented enhanced capillary density, reduced myocardial fibrosis and improved cardiac function. In conclusion, the present results demonstrated that the Shh pathway restored diabetic EPCs through the Shh/Bmi1/p53 axis, suppressed myocardial apoptosis and improved myocardial angiogenesis, thus reducing cardiac fibrosis and finally restoring myocardial repair and cardiac function in DMI. Thus, the Shh pathway may serve as a potential target for autologous cell therapy in diabetic myocardial ischemia.

Inflammatory Serine Proteases Play a Critical Role in the Early Pathogenesis of Diabetic Cardiomyopathy

“…2B-2D). Previous studies have demonstrated that pro-inflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), serve as chemotactic factors for leukocytes to diabetic cardiac tissue [31,32]. T1DM cardiac tissue demonstrated a statistically significant increase in the expression of all these cytokines (1.5 ± 0.02 and 1.3 ± 0.07 fold increase, respectively).…”

Targeting the Endothelium to Achieve Cardioprotection

“…Treatment of EPC with different molecules such as thymosin beta-4 ( Poh et al, 2020 ) and the overexpression of Sonic hedgehog (Q. Xiao et al, 2019 ) recover the reparative properties of EPC after MI in the context of diabetes by inducing their mobilization (restoring their circulating levels) or promoting angiogenesis. Shexiang Baoxing pills -a traditional Chinese medicine for ischemic heart disease- causes this same effect of EPC mobilization and promotion of angiogenesis when there are no other co-morbidities, but its capacity to mobilize EPC post-MI in a diabetic context has not been studied yet ( Huang et al, 2017 ).…”

BMI1 in the heart: Novel functions beyond tumorigenesis

“…Similarly, based on genetic lineage tracing analysis, in vivo experiments demonstrated that in a MI murine model, Bmi1 + progenitor cells resident in the heart underwent large proliferation and differentiation, resulting in de novo cardiac vasculature during post-MI ventricular remodeling, and depletion of these endothelial-related BMI1 + cells led to impaired angiogenesis and reduced ejection fraction, ultimately resulting in an ischemic-dilated cardiac phenotype [25] . BMI1 were also expressed in the diabetic endothelial progenitor cells (EPCs) and participated in diabetic myocardial infarction, experimental data showed that BMI1 was capable of mediating the antiapoptotic role of Shh pathway via inhibiting p53, and the activation of Shh/BMI1/p53 axis in diabetic EPCs markedly reduced EPC apoptosis and ameliorated EPC dysfunction, ultimately rescuing the diabetic myocardium under hypoxia [34] .…”

“… endothelial progenitor cells BMI1 mediates the benefits of the Shh pathway by inhibiting p53 in diabetic EPCs. [34] cardiac oxidative stress High levels of ROS enforced BMI1 + cardiac progenitor differentiation. Cardiac BMI1 + cells made up 25% of the CM-committed cells, which had the highest ROS levels of all adult cardiac progenitor cells.…”