Leukocytic toll-like receptor 2 knockout protects against diabetes-induced cardiac dysfunction

Antony

Medicinal Research Reviews

et al. 2020

The innate immune system contains multiple classes of pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in the intracellular and extracellular space. Although PRRs are indispensable for the detection and clearance of invading pathogens, dysregulated PRR activation by extrinsic and intrinsic factors leads to inflammatory diseases. PRRmediated inflammation has been shown to play a pivotal role in the pathogenesis of diabetic vascular complications (DVCs), which are the leading causes of morbidity and mortality in diabetic patients. Upon sensing hyperglycemiagenerated DAMPs, PRRs activate intracellular signaling pathways leading to the production of proinflammatory cytokines and chemokines in various cells of the kidney, brain, eye, and heart. The resulting chronic, low-grade inflammation contributes to DVCs. In this review, we summarize the role of PRRs in DVCs including diabetic nephropathy, neuropathy, retinopathy, and cardiomyopathy. We propose that targeting PRRs and associated signaling pathways may be beneficial for the management of DVCs.

Section: Tlrs In Diabetic Cardiomyopathymentioning

confidence: 99%

Section: Tlrs In Diabetic Cardiomyopathymentioning

confidence: 99%

Section: Evidence For a Role Of Prrs In Dvcsmentioning

confidence: 99%

See 1 more Smart Citation

Pattern recognition receptor‐mediated inflammation in diabetic vascular complications

Antony

Medicinal Research Reviews

et al. 2020

“…In diabetic mice, activation of TLR2 or 4 is associated with increased production of proin ammatory cytokines, pro-brotic molecules, proapoptotic markers, as well as cardiac dysfunction through binding to MyD88. [26][27][28][29][30] TLR3 and TLR6 has also been reported to promote high glucose-induced cardiomyocyte apoptosis [31] and NF-κB signaling, respectively.…”

Section: Discussionmentioning

confidence: 99%

Cardiac MyD88 Mediates Inflammatory Injury and Adverse Remodeling in Diabetes

Luo

Chen

et al. 2021

Preprint

Background: Hyperglycemia-associated inflammation contributes to adverse remodeling and fibrosis in diabetic heart. MyD88 is an adapter protein of many Toll-like receptors (TLRs) and is recruited to TLRs to initiate inflammatory signalling pathway in endotoxin-activated innate immunity. However, the role of MyD88 in diabetic cardiomyopathy is unknown. Methods: For genetic deficiency, cardiomyocyte-specific MyD88 knockout and littermate control mice were induced type 1 diabetes (T1D) by intraperitoneal injection of 50 mg/kg/day streptozotocin for five days consecutive and then fed for 4 moths. For pharmacological inhibition, MyD88 inhibitor LM8 were administered daily for 8 weeks by oral gavage in T1D and T2D (db/db) mice. The effect of genetic and pharmacological inhibition MyD88 to myocardial injure which were induced by 33 mM glucose in vivo.Results: In this study, we first found that MyD88 expression was increased in cardiomyocytes of diabetic mouse hearts. Cardiomyocyte-specific MyD88 knockout protected mice against hyperglycemia-induced cardiac inflammation, injury, hypertrophy, and fibrosis in T1D model. In cultured cardiomyocytes, MyD88 inhibition either by siRNA or by small-molecular inhibitor LM8 markedly blocked TLR4-MyD88 complex formation, reduced pro-inflammatory MAPKs/NF-κB cascade activation and decreased pro-inflammatory cytokine expression under high glucose condition. Moreover, pharmacologic inhibition of MyD88 by LM8 showed significantly anti-inflammatory, anti-hypertrophic and anti-fibrotic effects in the hearts of both T1D and T2D mice. These beneficial effects of MyD88 inhibition were correlated to the reduced activation of TLR4-MyD88-MAPKs/NF-κB signaling pathways in the hearts.Conclusion: Taken together, MyD88 in cardiomyocytes mediates diabetes-induced cardiac inflammatory injuries and genetic or pharmacologic inhibition of MyD88 shows significantly cardioprotective effects, indicating MyD88 as a potential therapeutic target for diabetic cardiomyopathy.

“…Animal studies have shown that knockout of TLR2 in a mouse model has significant benefits in diabetes-induced cardiac dysfunction (Lei et al, 2018). Moreover, TLR2 signaling leads to the activation of the key transcription factor NF-κB.…”

Section: Introductionmentioning

confidence: 99%

NOX1 promotes myocardial fibrosis and cardiac dysfunction via activating the TLR2/NF-κB pathway in diabetic cardiomyopathy

Zhang

Li²,

Wang³

et al. 2022

Front. Pharmacol.

Diabetic cardiomyopathy (DCM) is a prevalent complication in patients with diabetes, resulting in high morbidity and mortality. However, the molecular mechanisms of diabetic cardiomyopathy have yet to be fully elucidated. In this study, we investigated a novel target, NOX1, an isoform of superoxide-producing NADPH oxidase with key functional involvement in the pathophysiology of DCM. The DCM rat model was established by a high-fat diet combined with streptozotocin injections. DCM rats elicited myocardial fibrosis exacerbation, which was accompanied by a marked elevation of NOX1 expression in cardiac tissue. In particular, a specific NOX1 inhibitor, ML171, effectively decreased myocardial fibrosis and protected against cardiac dysfunction in DCM rats. Rat neonatal cardiac fibroblasts were incubated with high glucose (HG, 33 mM) as an in vitro model of DCM. We also observed that the expression of NOX1 was upregulated in HG-cultured cardiac fibroblasts. Silencing of NOX1 was found to attenuate myocardial fibrosis and oxidative stress in HG-induced cardiac fibroblasts. Furthermore, the upregulation of NOX1 by hyperglycemia induced activation of the TLR2/NF-κB pathway both in vitro and in vivo, whereas these effects were significantly attenuated with NOX1 gene silencing and further enhanced with NOX1 gene overexpression. In summary, we demonstrated that NOX1 induced activation of the TLR2/NF-κB pathway and increased reactive oxygen species production accumulation, which ultimately increased myocardial fibrosis and deteriorated cardiac function in diabetic cardiomyopathy. Our study revealed that NOX1 was a potential therapeutic target for DCM.