Background Sodium‐glucose cotransporter‐2 inhibitors are cardioprotective independent of glucose control, as demonstrated in animal models of acute myocardial ischemia and clinical trials. The functional and molecular mechanisms of these benefits in the setting of chronic myocardial ischemia are poorly defined. The purpose of this study is to determine the effects of canagliflozin therapy on myocardial perfusion, fibrosis, and function in a large animal model of chronic myocardial ischemia. Methods and Results Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (n=8) or 300 mg sodium‐glucose cotransporter‐2 inhibitor canagliflozin orally, daily (n=8). Treatment continued for 5 weeks, followed by hemodynamic measurements, harvest, and tissue analysis. Canagliflozin therapy was associated with increased stroke volume and stroke work and decreased left ventricular stiffness compared with controls. The canagliflozin group had improved perfusion to ischemic myocardium compared with controls, without differences in arteriolar or capillary density. Canagliflozin was associated with decreased interstitial and perivascular fibrosis in chronically ischemic tissue, with reduced Jak/STAT (Janus kinase/signal transducer and activator of transcription) signaling compared with controls. In ischemic myocardium of the canagliflozin group, there was increased expression and activation of adenosine monophosphate‐activated protein kinase, decreased activation of endothelial nitric oxide synthase, and unchanged total endothelial nitric oxide synthase. Canagliflozin therapy reduced total protein oxidation and increased expression of mitochondrial antioxidant superoxide dismutase 2 compared with controls. Conclusions In the setting of chronic myocardial ischemia, canagliflozin therapy improves myocardial function and perfusion to ischemic territory, without changes in collateralization. Attenuation of fibrosis via reduced Jak/STAT signaling, activation of adenosine monophosphate‐activated protein kinase, and antioxidant signaling may contribute to these effects.
Antigen presenting cells (APCs) initiate the immune response against cancer by engulfing and presenting tumor antigen to T cells. Our lab has recently developed a liposomal nanoparticle that binds complement C3 proteins, allowing it to bind to the complement C3 receptors of APCs and directly deliver antigenic peptides. APCs were shown to internalize and process complement C3bound liposomes containing ovalbumin (OVA), resulting in a significant increase in activated T cells that recognize OVA. Mice bearing A20-OVA lymphoma tumors were treated with OVAloaded C3-liposomes, which led to reduced tumor growth in both treated and distal tumors in all mice. Peripheral blood from treated mice had a lower percentage of immunosuppressive myeloid derived suppressor cells (MDSCs), a higher percentage of B cells, and increased anti-OVA IgG 1 levels compared to control mice. These results indicate that C3-liposome delivery of tumor antigen to APCs initiates a potent and systemic antitumor immune response.
Introduction: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have cardioprotective effects independent of glucose control, as demonstrated in animal models of acute myocardial ischemia and in clinical trials of patients with heart failure. The mechanisms of these effects require further investigation. The purpose of this study is to determine the effects of canagliflozin therapy on myocardial function, perfusion, and microvessel density in a large animal model of chronic myocardial ischemia. Methods: Yorkshire swine underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (CON, n=8) or 300mg canagliflozin (CANA) daily (n=8). Treatment continued for five weeks, followed by hemodynamic measurements and harvest. Perfusion, vessel density, and protein expression were measured by microsphere analysis, immunofluorescence, and immunoblotting respectively. Results: CANA therapy was associated with increased stroke volume (p=0.007) and stroke work (p=0.021), and decreased left ventricular stiffness (p=0.007) compared to CON. The CANA group had improved perfusion to ischemic myocardium at rest (p=0.036) and during pacing (p=0.038) compared to CON. There were no differences in arteriolar or capillary density between groups (p>0.5). In ischemic myocardium of the CANA group, there was increased expression of total AMPK (p=0.0047) and p-AMPK (p=0.038), decreased expression of p-eNOS (p=0.028) with unchanged total eNOS (p>0.5), and increased expression of antioxidant SOD2 (p<0.001) compared to CON. There were no differences in expression or activation of AKT and ERK1/2 (p>0.05). Conclusions: In the setting of chronic myocardial ischemia, canagliflozin therapy improves myocardial function and perfusion to ischemic territory, without changes in collateralization. Activation of AMPK and antioxidant signaling may contribute to these effects.
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