Stimulation of Soluble Guanylyl Cyclase (sGC) by Cinaciguat Attenuates Sepsisinduced Cardiac Injury

Background: Cinaciguat is a soluble Guanylyl Cyclase (sGC) activator that plays a crucial role in cardiovascular diseases. Previous research has shown that cinaciguat is involved in the progression of cardiomyopathy, which encompasses cardiac enlargement, heart dysfunction, and doxorubicin-induced heart damage. However, its therapeutic potential in sepsis-induced cardiomyopathy remains unknown.

Objectives: This study examined the impact of cinaciguat on Lipopolysaccharide (LPS)-induced myocardial injury and the underlying molecular mechanisms.

Methods: The mice model was established through intraperitoneal injection of LPS (10 mg/kg), and an in vitro model was generated by stimulating H9C2 cells with LPS (10 μg/ml) for 12 h. Subsequently, the sGC activator cinaciguat was used to assess its effects on LPS-induced cardiac injury. Additionally, echocardiography was conducted 12 hours after modeling to analyze cardiac function in mice. We used various methods to evaluate inflammation, and apoptosis, including Enzyme-Linked Immunosorbent Assay (ELISA), terminal deoxynucleotidyl transferase-mediated deoxyuridine Triphosphate Nick End Labeling (TUNEL) assay, Hematoxylin and Eosin (H&E) staining, western blotting and Real-Time Polymerase Chain Reaction (RT-PCR). Additionally, the protein kinase cGMP-dependent 1 (PRKG1)/cAMP-Response Element Binding protein (CREB) signaling pathway and Mitochondrial Ferritin (FtMt) in LPS-induced cardiac injury was assessed via Western blot analysis.

Results: LPS-induced cardiac dysfunction and increased levels of cardiac injury markers Cardiac Troponin T (cTnT) in vivo . This change was accompanied by an increase in inflammatory cytokines through Interleu-1β (IL-1β), Tumor Necrosis Factor α (TNF-α), and Interleu-6 (IL-6). The expression of apoptosis, such as cleaved caspase-3, Bax, and Bcl-2, was also upregulated. However, these effects were reversed via treatment with cinaciguat. Additionally, cinaciguat alleviated LPS-induced cardiac inflammation and apoptosis by activating the PRKG1/CREB signaling pathway, and promoting FtMt expression. The same results were also obtained in H9C2 cardiomyocytes.

Conclusion: We demonstrated that cinaciguat alleviated LPS-induced cardiac dysfunction, inflammation, and apoptosis through the PRKG1/CREB/FtMt pathway, thereby protecting against LPS-induced cardiac injury. This study identified a new strategy for treating cardiac injury caused by sepsis.