Nina Manian

Introduction. Sepsis is a life-threatening organ dysfunction attributed to dysregulated host immune response to infection. Septic shock is primarily caused by vasodilation and is characterized by SBP <90 mmHg and DBP <65 mmHg with signs of hypoperfusion. Sepsis-induced cardiomyopathy is seen in 13.8 to 40% of sepsis patients and contributes to shock and worsens survival.¹ The pathogenesis of sepsis-induced cardiomyopathy results from myocardial injury mediated by inflammatory cytokines and causes reversible myocardial dysfunction, characterized by ventricular dilation and decreased ejection fraction.² As many other studies have uncovered, the molecular basis of sepsis is complex and includes many different signaling molecules and inflammatory cells.² One important mediator that has been identified in the pathogenesis of sepsis-induced cardiomyopathy is interferon regulatory factor-2 binding protein 2 (IRF2BP2). IRF2BP2 is a negative regulator of inflammation and apoptosis. This study tests the hypothesis that overexpression of IRF2BP2 could be used as therapy to ameliorate sepsis-induced cardiomyopathy.⁴ Methods. The mouse model was utilized. Mice were administered intrapericardial injections of adeno-associated virus (AAV)9-IRF2BP2 and controls were administered AAV9-GFP injections.⁴ Four weeks after the initial intrapericardial injection, mice were administered intraperitoneal injections of lipopolysaccharide to induce sepsis. Measurements of myocardial function through echocardiogram and via a catheter placement into the left ventricle. At 6 or 12 hours after lipopolysaccharide administration, the mice were euthanized, and cells were collected for immunological staining. Results. Mice that overexpressed IRF2BP2 had increased myocardial function compared to control after administration of LPS. IRF2BP2 overexpressing mice demonstrated significantly improved ejection fraction, fractional shortening, and ventricular contractility compared to controls during sepsis. Levels of inflammatory cells, cytokines, and inflammatory mediators were also significantly reduced in mice that overexpressed IRF2BP2 as evidenced by immunohistochemistry. Experimental mice also showed decreased levels of apoptosis.⁴ Conclusion. This study identified that overexpression of IRF2BP2 can ameliorate sepsis-induced cardiomyopathy by decreasing expression of inflammatory markers, apoptosis, and lessening impairment of cardiac function as measured by ejection fraction, fractional shortening, and contractility. This suggests that targeting the myocardium with IRF2BP2 could potentially ameliorate sepsis-induced cardiomyopathy in humans.

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