Mechanisms and Therapeutic Prospects of Diabetic Cardiomyopathy Through the Inflammatory Response

From Frontiers via Jisc Publications RouterHistory: collection 2021, received 2021-04-13, accepted 2021-05-10, epub 2021-06-21Publication status: PublishedThe incidence of heart failure (HF) continues to increase rapidly in patients with diabetes. It is marked by myocardial remodeling, including fibrosis, hypertrophy, and cell death, leading to diastolic dysfunction with or without systolic dysfunction. Diabetic cardiomyopathy (DCM) is a distinct myocardial disease in the absence of coronary artery disease. DCM is partially induced by chronic systemic inflammation, underpinned by a hostile environment due to hyperglycemia, hyperlipidemia, hyperinsulinemia, and insulin resistance. The detrimental role of leukocytes, cytokines, and chemokines is evident in the diabetic heart, yet the precise role of inflammation as a cause or consequence of DCM remains incompletely understood. Here, we provide a concise review of the inflammatory signaling mechanisms contributing to the clinical complications of diabetes-associated HF. Overall, the impact of inflammation on the onset and development of DCM suggests the potential benefits of targeting inflammatory cascades to prevent DCM. This review is tailored to outline the known effects of the current anti-diabetic drugs, anti-inflammatory therapies, and natural compounds on inflammation, which mitigate HF progression in diabetic populations

Mechanisms and Therapeutic Prospects of Diabetic Cardiomyopathy Through the Inflammatory Response

The incidence of heart failure (HF) continues to increase rapidly in patients with diabetes. It is marked by myocardial remodeling, including fibrosis, hypertrophy, and cell death, leading to diastolic dysfunction with or without systolic dysfunction. Diabetic cardiomyopathy (DCM) is a distinct myocardial disease in the absence of coronary artery disease. DCM is partially induced by chronic systemic inflammation, underpinned by a hostile environment due to hyperglycemia, hyperlipidemia, hyperinsulinemia, and insulin resistance. The detrimental role of leukocytes, cytokines, and chemokines is evident in the diabetic heart, yet the precise role of inflammation as a cause or consequence of DCM remains incompletely understood. Here, we provide a concise review of the inflammatory signaling mechanisms contributing to the clinical complications of diabetes-associated HF. Overall, the impact of inflammation on the onset and development of DCM suggests the potential benefits of targeting inflammatory cascades to prevent DCM. This review is tailored to outline the known effects of the current anti-diabetic drugs, anti-inflammatory therapies, and natural compounds on inflammation, which mitigate HF progression in diabetic populations

The separate axes of TECPR1 and ATG16L1 in CASM

Conjugation of ATG8 to single membranes (CASM) is a fundamental cellular process that entails the conjugation of mammalian Atg8 homologs, here referred to as ATG8, to phosphatidylethanolamine (PE) and phosphatidylserine (PS) on endolysosomal compartments. Our current research, together with recent reports from the Randow, Wu, and Wileman labs, has uncovered yet another layer to this process. We discovered that, in addition to ATG16L1-containing complexes, TECPR1 (tectonin beta-propeller repeat containing 1)-containing ATG12–ATG5 E3 complexes can facilitate CASM, thereby providing a broader understanding of this pathway

Mechanisms and therapeutic prospects of diabetic cardiomyopathy through the inflammatory response

The incidence of heart failure (HF) continues to increase rapidly in patients with diabetes. It is marked by myocardial remodeling, including fibrosis, hypertrophy, and cell death, leading to diastolic dysfunction with or without systolic dysfunction. Diabetic cardiomyopathy (DCM) is a distinct myocardial disease in the absence of coronary artery disease. DCM is partially induced by chronic systemic inflammation, underpinned by a hostile environment due to hyperglycemia, hyperlipidemia, hyperinsulinemia, and insulin resistance. The detrimental role of leukocytes, cytokines, and chemokines is evident in the diabetic heart, yet the precise role of inflammation as a cause or consequence of DCM remains incompletely understood. Here, we provide a concise review of the inflammatory signaling mechanisms contributing to the clinical complications of diabetes-associated HF. Overall, the impact of inflammation on the onset and development of DCM suggests the potential benefits of targeting inflammatory cascades to prevent DCM. This review is tailored to outline the known effects of the current anti-diabetic drugs, anti-inflammatory therapies, and natural compounds on inflammation, which mitigate HF progression in diabetic populations

Multi-organ FGF21-FGFR1 signaling in metabolic health and disease

Metabolic syndrome is a chronic systemic disease that is particularly manifested by obesity, diabetes, and hypertension, affecting multiple organs. The increasing prevalence of metabolic syndrome poses a threat to public health due to its complications, such as liver dysfunction and cardiovascular disease. Impaired adipose tissue plasticity is another factor contributing to metabolic syndrome. Emerging evidence demonstrates that fibroblast growth factors (FGFs) are critical players in organ crosstalk via binding to specific FGF receptors (FGFRs) and their co-receptors. FGFRs activation modulates intracellular responses in various cell types under metabolic stress. FGF21, in particular is considered as the key regulator for mediating systemic metabolic effects by binding to receptors FGFR1, FGFR3, and FGFR4. The complex of FGFR1 and beta Klotho (β-KL) facilitates endocrine and paracrine communication networks that physiologically regulate global metabolism. This review will discuss FGF21-mediated FGFR1/β-KL signaling pathways in the liver, adipose, and cardiovascular systems, as well as how this signaling is involved in the interplay of these organs during the metabolic syndrome. Furthermore, the clinical implications and therapeutic strategies for preventing metabolic syndrome and its complications by targeting FGFR1/β-KL are also discussed

FGF21/FGFR1-β-KL cascade in cardiomyocytes modulates angiogenesis and inflammation under metabolic stress

Diabetes is a metabolic disorder with an increased risk of developing heart failure. Inflammation and damaged vasculature are the cardinal features of diabetes-induced cardiac damage. Moreover, systemic metabolic stress triggers discordant intercellular communication, thus culminating in cardiac dysfunction. Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone transducing cellular signals via fibroblast growth factor receptor 1 (FGFR1) and its co-receptor beta-klotho (β-KL). This study first demonstrated a decreased expression or activity of FGFR1 and β-KL in both human and mouse diabetic hearts. Reinforcing cardiac FGFR1 and β-KL expression can alleviate pro-inflammatory response and endothelial dysfunction upon diabetic stress. Using proteomics, novel cardiomyocyte-derived anti-inflammatory and proangiogenic factors regulated by FGFR1-β-KL signaling were identified. Although not exhaustive, this study provides a unique insight into the protective topology of the cardiac FGFR1-β-KL signaling-mediated intercellular reactions in the heart in response to metabolic stress

TECPR1 is activated by damage-induced sphingomyelin exposure to mediate noncanonical autophagy

Cells use noncanonical autophagy, also called conjugation of ATG8 to single membranes (CASM), to label damaged intracellular compartments with ubiquitin-like ATG8 family proteins in order to signal danger caused by pathogens or toxic compounds. CASM relies on E3 complexes to sense membrane damage, but so far, only the mechanism to activate ATG16L1-containing E3 complexes, associated with proton gradient loss, has been described. Here, we show that TECPR1-containing E3 complexes are key mediators of CASM in cells treated with a variety of pharmacological drugs, including clinically relevant nanoparticles, transfection reagents, antihistamines, lysosomotropic compounds, and detergents. Interestingly, TECPR1 retains E3 activity when ATG16L1 CASM activity is obstructed by the Salmonella Typhimurium pathogenicity factor SopF. Mechanistically, TECPR1 is recruited by damage-induced sphingomyelin (SM) exposure using two DysF domains, resulting in its activation and ATG8 lipidation. In vitro assays using purified human TECPR1-ATG5-ATG12 complex show direct activation of its E3 activity by SM, whereas SM has no effect on ATG16L1-ATG5-ATG12. We conclude that TECPR1 is a key activator of CASM downstream of SM exposure