SGLT2 Inhibitor-pretreated Macrophage Transplantation Improves Adverse Ventricular Remodeling After Acute Myocardial Infarction

Abstract

Macrophages play an important role in the progression of acute myocardial infarction (AMI). Studies have shown that sodium-dependent glucose transporter 2 inhibitor (SGLT2i) after AMI could increase the proportion of M2 type/M1 macrophages and reduces adverse ventricular remodeling (AVR) post AMI. This study aimed to investigate whether SGLT2i-pretreated macrophage transplantation could reduce AVR after AMI and the underlying mechanisms. C57BL/6 mice were used to establish an AMI model by ligating the coronary arteries. Dynamic observation of transplanted bone marrow-derived macrophages (BMDMs) was performed using an in vivo imaging system (IVIS). Cardiac function was assessed using echocardiography. The fibrosis ratio was measured using Masson’s trichrome staining. Cardiomyocyte apoptosis was measured using the TUNEL assay. Macrophage subtypes were measured using flow cytometry. We detected the expression of inflammatory factors in the myocardium and serum using enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). IVIS revealed that transplanted SGLT2i-pretreated BMDMs were present in the infarcted myocardium for 7 d. Flow cytometry revealed that SGLT2i-pretreated BMDMs promoted the conversion of native-derived macrophages to the M2-type. SGLT2i-pretreated BMDMs also reduced inflammatory factors (IL-6, TNFα, and IL-1β) in the infarcted myocardium and serum. At 28 d post-AMI, SGLT2i-pretreated BMDMs increased cardiac function and vascular density, but reduced cardiomyocyte hypertrophy. SGLT2i-pretreated BMDMs could reduce cardiomyocyte apoptosis and fibrotic area ratio. In conclusion, transplanted SGLT2i-pretreated BMDMs were present in the infarcted myocardium for 7 d and improved AVR by reducing inflammation and modulating the conversion of native mice-derived macrophages to M2-type macrophages.

Efficacy of Sodium-Glucose Cotransporter 2 Inhibitors in Patients with Acute Coronary Syndrome

“…Although there is no pooled analysis of clinical trials focusing on the efficacy of SGLT2i in ACS patients, recent experimental evidence has shown that SGLT2i treatment reduces myocardial infarct size, alleviates intramyocardial hemorrhage, and improves adverse ventricular remodeling after acute myocardial infarction in animal models. − A recent review concluded that the potential mechanisms of SGLT2i may be beneficial for patients with an acute myocardial infarction. However, this has not yet been adequately investigated in clinical trials .…”

“…57, 95% CI [−1.00, −0.15], p = 0.008) and canagliflozin (MD −0.63, 95% CI [−0.92, −0.34], p < 0.0001) subgroups, in the subgroups with a treatment duration ≥1 year (MD −0.47, 95% CI [−0.75, −0.20], p = 0.0007) and ≤3 months (MD −0.63, 95% CI [−0.92, −0.34], p < 0.0001), and in the subgroup with a mean age of <63 years (MD −0.57, 95% CI [−1.00, −0.15], p = 0.008). SGLT2i had no significant effect in the empagliflozin subgroup (MD −0.10, 95% CI [−0.40, 0.20], p = 0.51), in the subgroup with a treatment duration of 24 weeks to 1 year (MD −0.52, 95% CI [−1.12, 0.08], p = 0.09), and in the subgroup with a mean age of ≥63 years (MD −0.37, 95% CI [−0.89, 0.15], p = 0.17) (TableS9).…”

The effect of macrophages and their exosomes in ischemic heart disease

“…Chen et al pre-treated bone marrow-derived macrophages with a sodiumdependent glucose transporter 2 inhibitor (SGLT2i) before transplantation into a mouse model of MI. This resulted in the suppression of inflammation, reduction of myocardial cell apoptosis, and promotion of the transformation of native cardiac macrophages into the M2 phenotype, which contributed to the reduction of adverse ventricular remodeling after MI (149). Similarly, Podaru et al stimulated bone marrow-derived monocytes with macrophage colony-stimulating factor (M-CSF) and IL-4 to induce their differentiation into M2 macrophages before transplantation, resulting in significant improvement in cardiac function and structure in MI mice.…”