Therapeutic contribution of melatonin to the treatment of septic cardiomyopathy: A novel mechanism linking Ripk3-modified mitochondrial performance and endoplasmic reticulum function

Abstract

The basic pathophysiological mechanisms underlying septic cardiomyopathy have not yet been completely clarified. Disease-specific treatments are lacking, and care is still based on supportive modalities. The aim of our study was to assess the protective effects of melatonin on septic cardiomyopathy, with a focus on the interactions between receptor-interacting protein kinase 3 (Ripk3), the mitochondria, endoplasmic reticulum (ER) and cytoskeletal degradation in cardiomyocytes. Ripk3 expression was increased in heart samples challenged with LPS, followed by myocardial inflammation, cardiac dysfunction, myocardial breakdown and cardiomyocyte death. The melatonin treatment attenuated septic myocardial injury in a comparable manner to the genetic depletion of Ripk3. Molecular investigations revealed that Ripk3 intimately regulated mitochondrial function, ER stress, cytoskeletal homeostasis and cardioprotective signaling pathways. Melatonin-mediated inhibition of Ripk3 improved mitochondrial bioenergetics, reduced mitochondria-initiated oxidative damage, sustained mitochondrial dynamics, ameliorated ER stress, normalized calcium recycling, and activated cardioprotective signaling pathways (including AKT, ERK and AMPK) in cardiomyocytes. Interestingly, Ripk3 overexpression mediated resistance to melatonin therapy following the infection of LPS-treated hearts with an adenovirus expressing Ripk3. Altogether, our findings identify Ripk3 upregulation as a novel risk factor for the development of sepsis-related myocardial injury, and melatonin restores the physiological functions of the mitochondria, ER, contractile cytoskeleton and cardioprotective signaling pathways. Additionally, our data also reveal a new, potentially therapeutic mechanism by which melatonin protects the heart from sepsis-mediated dysfunction, possibly by targeting Ripk3.

RETRACTED: Mammalian STE20-Like Kinase 2 Promotes Lipopolysaccharides-Mediated Cardiomyocyte Inflammation and Apoptosis by Enhancing Mitochondrial Fission

“…Myocardial inflammation is the hallmark of several cardiovascular disorders, such as myocardial infarction, myocardial ischemia-reperfusion injury, diabetic cardiomyopathy, and sepsis-related myocardial damage (Gebhard et al, 2018;Zhong et al, 2019). The immune cells and pro-inflammatory cytokines involved in the inflammatory process promote cardiomyocyte dysfunction, which contributes to cardiovascular disease progression, severity, and outcomes (Ziegler, 2005).…”

Treatment of ebola and other infectious diseases: melatonin “goes viral”

“…As additional justification for the use of melatonin to treat Ebola infections, it is well known that similar vascular damage induced by bacterial lipopolysaccharide also is ameliorated by melatonin. This has been repeatedly documented in experimental sepsis (68,69) and has also been observed in human newborns suffering with septic shock (70).…”

“…Again, front and center are the ability of melatonin to inhibit pro-inflammatory cytokines, reduce oxidative stress, and support the immune system which synergistically would afford protection against the complications induced by the Ebola virus. Additionally, Andersen and co-workers (53) reminded the reader that under similar pathological circumstances of bacterial lipopolysaccharide toxicity melatonin maintains more normal endothelial function and reduces fatality as mentioned above (68)(69)(70).…”

Current Status of Septic Cardiomyopathy: Basic Science and Clinical Progress

“…Receptor-interacting protein kinase3 (Ripk3) may regulate signaling pathways that are related to mitochondrial injury, endoplasmic reticulum stress, and cell scaffold balance. Zhong et al (2019) found that Ripk3 expression was increased in LPS-infected cardiomyocytes. Mitochondrial autophagy plays an integral role in cardiac dysfunction.…”

“…Melatonin can restore the physiological functions of mitochondria and endoplasmic reticulum, maintain the stability of cytoskeleton, and thus improve cardiac function in septic mice (Zhang et al, 2019). The study on molecular mechanism has shown that melatonin attenuates the expression of BAP31 that interacts with mitochondria-localized proteins and regulates mitochondrial function (Zhang et al, 2019;Zhong et al, 2019). Kokkinaki et al (2019) showed that chemically synthesized diglucoside (LGM2605) can reduce the accumulation of cardiac ROS, protect mitochondrial function in heart, reverse myocardial injury, and improve the survival rate in a mouse model of sepsis.…”