Levosimendan ameliorates cardiomyocyte injury and mitochondrial dysfunction in an Nrf2-dependent manner in mice with sepsis-induced cardiomyopathy

Sepsis-induced cardiomyopathy (SIC) is a severe complication of sepsis and septic shock and is characterized by cardiac dysfunction. Levosimendan (LEVO), a calcium sensitizer, has shown therapeutic potential in SIC, although its underlying mechanism remains unclear. Nrf2, a pivotal regulator of antioxidant and anti-inflammatory responses, may represent a potential target for SIC treatment. In this study, we examine the effects of LEVO on SIC and explore the mechanistic role of Nrf2 in mediating its cardioprotective effects. A murine SIC model is established via cecal ligation and puncture (CLP), and cardiomyocyte injury is induced <i>in vitro</i> via lipopolysaccharide (LPS) exposure in HL-1 cells. The CLP procedure significantly elevates serum cTnI and IL-6 levels and reduces the survival rates of mice. Echocardiographic analysis reveals impaired cardiac structure and function, accompanied by mitochondrial morphological and functional damage, in SIC mice. Interestingly, these pathological changes in SIC are markedly attenuated by LEVO treatment. Similarly, LEVO administration restores proliferative capacity; increases mitochondrial ATP, mitochondrial membrane potential (MMP) and NADH levels; and reduces ROS production and intracellular calcium overload. Notably, the protective effects of LEVO on cardiomyocyte viability and mitochondrial function are significantly diminished following Nrf2 inhibition or <i>Nrf2</i> knockout (KO). Collectively, these findings demonstrate that LEVO mitigates cardiomyocyte injury and mitochondrial dysfunction in SIC through an Nrf2-dependent mechanism.