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  • Heart failure affects approximately million

    2021-10-11

    Heart failure affects approximately 6.5 million people over 20 years of age in the United States, with its prevalence estimated to increase about 45% by 2030 to almost 8 million . It is a chronic disease with complex etiology and heterogeneity in its pathological manifestations. Major risk factors for heart failure include smoking, hypertension, and obesity, as well as lifestyle and dietary influences. Despite significant advancement in the standard care of heart failure, the 5-year mortality rate of the disease remains at nearly 50% . The new effective therapies for heart failure are critically needed for such a major unmet need. Glucagon (GLC) is a peptide hormone produced by pancreatic α-cells , , , , . As a major catabolic hormone, GLC stimulates glucose production from glycogen in liver and promotes gluconeogenesis while it inhibits glycolysis and glycogen synthesis . It increases blood glucose and Clonidine HCl mg expenditure as part of the energy mobilization process in response to hypoglycemia and other bioenergetic stress. Consequently, GLC serves as a counterbalancing hormone with insulin to regulate glucose homeostasis depending on nutrient conditions and available energy sources . The GLC receptor (GCGR) is a member of the G protein–coupled receptor family , , , . The canonical function of GCGR elicited by GLC is mediated by G protein–coupled protein kinase A activation; however, tissue-specific function of GCGR has been implicated in different cellular processes , , . Elevated GLC is observed in chronic hyperglycemia associated with type 1 or type 2 diabetes , , . Overactivated GLC signaling may contribute to disease progression of diabetes by enhancing glucose production and aggravating systemic hyperglycemia, as well as impairing insulin signaling. Therefore, GCGR inhibition, using either small molecules or antagonistic antibodies, is potentially efficacious to treat diabetes as demonstrated in both preclinical studies as well as several recent clinical trials , , , , , , , , , , . However, much of the previous studies on GLC signaling are in the liver and brain, involving glucose metabolic regulation , , . Its specific and cell-autonomous role in cardiac tissue has just begun to be appreciated. Other than glucose regulation in liver, GCGR is also widely expressed in multiple other tissues, including the heart , , , , , , , , . In a recent study by Ali et al. , GLC stimulation was shown to promote ischemia injury in mouse heart while cardiomyocyte specific GCGR inactivation protected the heart from pathological remodeling following myocardial infarction. This study highlights the potential cardiomyocyte cell-autonomous effect of GCGR overactivation in cardiac pathological remodeling, and GCGR antagonism as a potential therapy for heart failure. REMD-477 is a fully human anti-GCGR antibody that competitively blocks GLC binding to the GCGR with 30-pM binding affinity, and can effectively inhibit the receptor activity at low nanomolar concentrations in cell-based functional assays , , . Compared with small-molecule approaches , antibody-based GCGR antagonism such as REMD-477 is a competitive antagonist and does not have deleterious effects on serum lipid profiles , , , , . Finally, REMD-477 has been shown to be safe in a phase I study () and is being tested in 2 phase II clinical studies ( and for type 1 and type 2 diabetes, respectively). In short, anti-GCGR antibody offers a novel tool to effectively and specifically inhibit GCGR with proven record of clinical safety and efficacy at molecular and metabolic levels. Functionally identical as REMD-477, REMD2.59 is a surrogate human antibody specifically generated for preclinical studies in rodents . In a recent study, weekly treatment with REMD2.59 is shown to reverse diabetes in mice and improves cardiac function associated with diabetic cardiomyopathy . Although this study supports the cardioprotective effect of GCGR antagonism, it is not clear whether the beneficial effect is a direct consequence of cardioprotection on cardiomyocyte or an indirect result of improved global glucose homeostasis and insulin signaling. In the current study, we employed 2 mechanistically divergent and diabetes-independent murine disease models for heart failure, myocardial infarction, and pressure overload, to test whether the cardioprotection by the GCGR antibody is the primary effect of the receptor inhibition. Based on morphological, functional, and molecular parameters, treatment with GCGR antibody REMD2.59 significantly ameliorated the development of heart failure, by attenuating pathological remodeling and cardiac hypertrophy while preventing functional deterioration and pathological gene expression. These novel and exciting observations implicate a potential role of GLC-mediated signaling in heart failure via a cardiomyocyte cell-autonomous mechanism. It raises the prospect of targeting GCGR as potential therapy to treat common forms of heart failure independent of the confounding status of global glucose metabolic disorders.