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  • br Do the actions of GLP R agonists on

    2022-03-12


    Do the actions of GLP-1R agonists on the vascular endothelium account for GLP-1R agonist-mediated cardioprotection? The previous section highlighted the recent clinical evidence from cardiovascular outcomes studies supporting the notion that GLP-1R agonists confer cardioprotective actions in patients with T2D. In spite of these exciting findings, we currently have limited knowledge on the actual mechanisms of action responsible for these actions. We have recently described how optimizing myocardial Edrophonium chloride receptor metabolism via indirect actions on the myocardium could account for GLP-1R agonist-induced cardioprotection [1], though anti-inflammatory actions and improvements in cardiovascular risk factors (e.g. circulating lipid levels) could also account for such cardioprotection [17,41,56]. In contrast, the actions of GLP-1/GLP-1R agonists on the vascular endothelium could also contribute to GLP-1R agonist-induced cardioprotection in subjects with T2D. It is well established that reductions in SBP/DBP lead to marked reductions in cardiovascular risk in human subjects [19]. Moreover, the potential actions of GLP-1R agonism on VSMC proliferation and/or oxidative stress would be anticipated to contribute to attenuated progression of atherosclerotic lesion progression as has been observed in preclinical studies [2,49,50,60], which would have favorable actions on cardiovascular outcomes. Increased microvascular recruitment and microvascular blood flow within the myocardium’s coronary vasculature is likely to improve oxygen and nutrient delivery to the heart, which would be advantageous for a T2D subject comorbid for angina/ischemic heart disease and/or heart failure. Likewise, this could also improve insulin delivery to the cardiac myocytes within the myocardium, and thereby account for potential GLP-1R agonist-induced improvements in myocardial energy metabolism that augment contractile efficiency [1]. Hence, vascular/endothelial GLP-1R activity may potentially play a key role in GLP-1R agonist-induced cardioprotection, though further work is necessary to determine what cell types within the vascular endothelium express a full-length and functional GLP-1R that mediate such actions. Although GLP-1(9–36) or GLP-1(28–36) at pharmacological concentrations may have direct actions on ECs that improve endothelial function and could protect against ischemic heart disease and/or heart failure, this is an unlikely mechanism for liraglutide’s or semaglutide’s positive effects on cardiovascular outcomes in subjects with T2D. As both liraglutide and semaglutide are acylated, they noncovalently associate with serum albumin in the circulation, and are thus highly resistant to DPP-4-mediated cleavage. Thus, direct actions of these GLP-1R agonists on the vascular endothelium, or their other proposed cardioprotective mechanisms (e.g. reduced inflammation, improved energy metabolism) are more likely to account for their salutary actions on cardiovascular outcomes in subjects with T2D. Similar conclusions likely pertain to other preclinical studies utilizing DPP-4 resistant GLP-1R agonists such as exenatide, albiglutide, or lixisenatide. Conversely, one must be cautious when interpreting the vascular/endothelial contributions to cardioprotection in preclinical and clinical studies elicited via treatment with native GLP-1, which is metabolized to GLP-1(9–36). Nevertheless, identifying the precise cardioprotective mechanism(s) of action through clinical studies will prove difficult due to GLP-1R agonists affecting multiple organ systems following systemic administration. As such, sophisticated preclinical studies using cell/tissue-specific deficient mouse models for the Glp1r in experimental models of T2D and various cardiovascular disease, in response to treatment with GLP-1R agonists or placebo will be required to shed light on whether vascular/endothelial mechanisms truly contribute to GLP-1R agonist-induced cardioprotection.
    Summary