Sepsis-induced myocardial dysfunction promotes reversible myocardial depression akin to stress-induced cardiomyopathy, known as Takotsubo cardiomyopathy. The precise pathophysiological mechanisms underlying both sepsis and stress cardiomyopathy remain elusive. Systemic inflammation and oxidative stress likely contribute to the development of cardiac dysfunction. Sodium-glucose cotransporter 2 (SGLT2), a foundational therapy of heart failure, has anti-inflammatory properties and improves endothelial dysfunction.

To explore the potential causal link between sepsis and Takotsubo syndrome, LPS-induced endothelial and cardiac dysfunction were studied and the role of SGLT2 was investigated.

Porcine coronary endothelial cells (PCAECs) and rat left ventricle specimens were exposed to LPS or ß-adrenoreceptor agonist isoproterenol for 24h. The formation of reactive oxygen species (ROS) was assessed using dihydroethidium staining, nitric oxide (NO) by DAF-FM, expression levels of genes and proteins by RT-qPCR, Western blot and immunofluorescence staining, respectively, and adhesion using THP1, a human monocytic cell line, and platelets.

Exposure of PCAECs to LPS for 24h caused a pro-oxidant response, reduced basal and bradykinin-stimulated endothelial formation of NO, stimulated NF-κB nuclear translocation, and increased THP-1 cells and platelets adhesion. These effects were blocked by N-acetylcysteine (NAC), losartan (AT1R antagonist), VAS-2870 (NADPH oxidases inhibitor), sotagliflozin (dual SGLT1 and SGLT2 inhibitor) and empagliflozin (SGLT2 inhibitor). LPS-induced pro-oxidant responses were also inhibited by antagonist of TLR2 and inhibitors of TLR4 and RAGE. While SGLT2 inhibition prevented the 24h pro-oxidant response to LPS, it had no effect on the 1h response. LPS upregulated SGLT2 protein expression and inhibited that of eNOS in a concentration dependent manner whereas VCAM-1 protein levels were increased in response to low concentrations of LPS and decreased at higher ones. Exposure of LV specimens to either LPS or isoproterenol for 24h caused strong pro-oxidant responses.

The findings indicate that LPS promoted a pro-oxidant response, endothelial dysfunction and increase monocyte and platelets adhesion in coronary endothelial cells involving the angiotensin II type 1 receptor (AT1R)-mediated activation of NADPH oxidases and SGLT2 pro-oxidant pathway. A similar pro-oxidant response was seen in cardiac LV. Targeting SGLT2 inhibition emerges as a promising strategy for treating septic cardiovascular dysfunction.