Systemic Delivery of siRNA Specific for Silencing TLR4 Gene Expression Reduces Diabetic Cardiomyopathy in a Mouse Model of Streptozotocin-Induced Type 1 Diabetes

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.

“…70,[75][76][77] In addition, data from preclinical studies indicate that disrupting TLR activation provides beneficial effects in diabetic nephropathy 78 and cardiomyopathy. 79,80…”

Section: Clrsmentioning

confidence: 99%

“…The correlation between TLR activation and DVCs has been addressed in many studies 70,75–77 . In addition, data from preclinical studies indicate that disrupting TLR activation provides beneficial effects in diabetic nephropathy 78 and cardiomyopathy 79,80 …”

Section: Evidence For a Role Of Prrs In Dvcsmentioning

confidence: 99%

Pattern recognition receptor‐mediated inflammation in diabetic vascular complications

Antony

Medicinal Research Reviews

et al. 2020

Evidence-Based Complementary and Alternative Medicine

“…Myocardial hypertrophy and fibrosis are among the most representative changes in DCM [25,26]. In DCM, the dynamic balance between synthesis and deposition of the myocardial extracellular matrix is disturbed, and excessive deposition of collagen and an imbalance in the collagen ratio lead to cardiac remodeling [27][28][29].…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Huangqi Shengmai Yin on Type 1 Diabetes-Induced Cardiomyopathy by Improving Myocardial Lipid Metabolism

Cao

Pan

Sui

et al. 2021

Diabetic cardiomyopathy (DCM) is one of the many complications of diabetes. DCM leads to cardiac insufficiency and myocardial remodeling and is the main cause of death in diabetic patients. Abnormal lipid metabolism plays an important role in the occurrence and development of DCM. Huangqi Shengmai Yin (HSY) has previously been shown to alleviate signs of heart disease. Here, we investigated whether HSY could improve cardiomyopathy caused by type 1 diabetes mellitus (T1DM) and improve abnormal lipid metabolism in the diabetic heart. Streptozotocin (STZ) was used to establish the T1DM mouse model, and T1DM mice were subsequently treated with HSY for eight weeks. The changes in the cardiac conduction system, histopathology, blood myocardial injury indices, and lipid content and expression of proteins related to lipid metabolism were evaluated. Our results showed that HSY could improve electrocardiogram; decrease the serum levels of CK-MB, LDH, and BNP; alleviate histopathological changes in cardiac tissue; and decrease myocardial lipid content in T1DM mice. These results indicate that HSY has a protective effect against T1DM-induced myocardial injury in mice and that this effect may be related to the improvement in myocardial lipid metabolism.

Front. Cardiovasc. Med.

“…The low-grade inflammation appears to be central as several experimental anti-inflammatory approaches, particularly involving the TLR4/MD2 pathway, prevent the development of DCM ( 19 ). Moreover, systemic interference of TLR4 expression using siRNA also prevents the development of DCM in STZ-treated mice ( 21 ). Despite these successful interventions, there are only a few articles linking TLR signaling with the pathogenesis of cardiac diseases.…”

Section: Discussion and Future Perspectivesmentioning

confidence: 99%

“…In neonatal rat cardiomyocytes, oxidized low density lipoproteins (ox-LDL) also induce TLR4 and NF-κB-dependent apoptosis ( 20 ). Moreover, global silencing of TLR4, using a systemic administration of TLR4 siRNA, prevents a decline in the systolic function and the ventricular remodeling reported for STZ-treated mice ( 21 ). Therefore, TLRs can be considered as a molecule of interest in the pathophysiology of DCM.…”

Section: Inflammation In the Pathogenesis Of Dcmmentioning

confidence: 98%

Novel Insights Into the Pathogenesis of Diabetic Cardiomyopathy and Pharmacological Strategies

Muñoz-Cordova

Hernández‐Fuentes

López-Crisosto

et al. 2021

Diabetic cardiomyopathy (DCM) is a severe complication of diabetes developed mainly in poorly controlled patients. In DCM, several clinical manifestations as well as cellular and molecular mechanisms contribute to its phenotype. The production of reactive oxygen species (ROS), chronic low-grade inflammation, mitochondrial dysfunction, autophagic flux inhibition, altered metabolism, dysfunctional insulin signaling, cardiomyocyte hypertrophy, cardiac fibrosis, and increased myocardial cell death are described as the cardinal features involved in the genesis and development of DCM. However, many of these features can be associated with broader cellular processes such as inflammatory signaling, mitochondrial alterations, and autophagic flux inhibition. In this review, these mechanisms are critically discussed, highlighting the latest evidence and their contribution to the pathogenesis of DCM and their potential as pharmacological targets.