Spleen tyrosine kinase‑induced JNK‑dependent NLRP3 activation is involved in diabetic cardiomyopathy

Abstract

diabetic cardiomyopathy (dcM) is a leading contributor to the increased morbidity and mortality rates associated with diabetes. Persistent inflammation has previously been reported to be involved in the pathogenesis of DCM. However, the exact underlying molecular mechanisms remain to be fully elucidated. In the present study, the role of spleen tyrosine kinase (Syk) and c-Jun N-terminal kinase (JNK) in NLR family pyrin domain-containing 3 (NLRP3 inflammasome) activation in DCM were investigated in vivo and in vitro. Streptozotocin (65 mg/kg) was injected intraperitoneally into Sprague-Dawley rats to induce a rat model of diabetes. Neonatal rat cardiomyocytes and H9c2 cells were cultured to detect the expression of JNK, NLRP3 and its associated downstream molecules, following treatment with Syk/JNK inhibitor or Syk/JNK-small interfering (si)RNA in high glucose (HG) conditions. It was revealed that the protein and mRNA expression levels of phospho (p)-Syk, p-JNK, NLRP3 and its associated downstream molecules, including interleukin (IL)-1β, were upregulated in vivo and in vitro. The JNK inhibitor significantly decreased the expression of NLRP3 and its downstream molecules in neonatal rat cardiomyocytes and H9c2 cells treated with HG. Furthermore, Syk-siRNA and the Syk inhibitor markedly inhibited the HG-induced activation of JNK, followed by the downregulation of NLRP3 and its downstream molecules at the mRNA and protein levels in cells. Therefore, it was demonstrated that the HG-induced activation of NLRP3 was mediated by the activation of Syk/JNK, which subsequently increased the protein expression levels of mature IL-1β, suggesting that the Syk/JNK/NLRP3 signaling pathway serves a critical role in the pathogenesis of DCM.

Pattern recognition receptor‐mediated inflammation in diabetic vascular complications

“…In long-standing diabetes, cardiac and vascular injury is, to a large extent, caused by HG-activated NLRP3 inflammasome, which drives inflammatory responses by not only inducing cytokines, such as IL-1β and IL-18, but also causing pyroptosis. 137,157,158 Hyperglycemia has been shown to activate the NLRP3 inflammasome in various cell populations of the heart, including cardiomyocytes and cardiofibroblasts, 157,[159][160][161] leading to cardiac inflammation, fibrosis, and apoptosis. 162,163 HG-induced activation of NLRP3 can also be regulated by Syk/JNK and TLR4/ NF-κB pathways.…”

“…162,163 HG-induced activation of NLRP3 can also be regulated by Syk/JNK and TLR4/ NF-κB pathways. 159,161 Cardiac dysfunction in T2DM animal models can be ameliorated by dapagliflozin and rosuvastatin, and these protective effects are likely mediated through the inhibition of NLRP3 inflammasome. 162,163 Furthermore, knockdown of NOD2 supresses myocardial fibrosis and cell apoptosis in diabetic mice.…”

“…Hyperglycemia has been shown to activate the NLRP3 inflammasome in various cell populations of the heart, including cardiomyocytes and cardiofibroblasts, 157,159–161 leading to cardiac inflammation, fibrosis, and apoptosis 162,163 . HG‐induced activation of NLRP3 can also be regulated by Syk/JNK and TLR4/NF‐κB pathways 159,161 . Cardiac dysfunction in T2DM animal models can be ameliorated by dapagliflozin and rosuvastatin, and these protective effects are likely mediated through the inhibition of NLRP3 inflammasome 162,163 .…”

Exercise as A Potential Therapeutic Target for Diabetic Cardiomyopathy: Insight into the Underlying Mechanisms

“…These changes are key factors leading to cardiac hypertrophy, cardiac remodeling, and heart failure in DCM [17,86]. The c-Jun N-terminal kinases (JNKs) group of mitogen-activated protein kinases (MAPKs) are activated under the conditions of metabolic disorders and T2DM [20,[87][88][89][90]. The JNKs promote apoptosis in cardiomyocytes by activating the pro-apoptotic proteins caspase 8 and Bax [72].…”

Exercise as A Potential Therapeutic Target for Diabetic Cardiomyopathy: Insight into the Underlying Mechanisms

“…These changes are key factors leading to cardiac hypertrophy, cardiac remodeling, and heart failure in DCM [17,78]. The c-Jun N-terminal kinases (JNKs) group of mitogen-activated protein kinases (MAPKs) are activated under the conditions of metabolic disorders and T2DM [20,[79][80][81][82]. The JNKs promote apoptosis in cardiomyocytes by activating the pro-apoptotic proteins caspase 8 and Bax [57].…”