RESUMO
Type 2 diabetes (T2D) and obesity represent entangled pandemics that accelerate the development of cardiovascular disease (CVD). Given the immense burden of CVD in society, non-invasive prevention and treatment strategies to promote cardiovascular health are desperately needed. During T2D and obesity, chronic dysglycemia and abnormal adiposity result in systemic oxidative stress and inflammation that deplete the vascular regenerative cell reservoir in the bone marrow that impairs blood vessel repair and exacerbates the penetrance of CVD co-morbidities. This novel translational paradigm, termed 'regenerative cell exhaustion' (RCE), can be detected as the depletion and dysfunction of hematopoietic and endothelial progenitor cell lineages in the peripheral blood of individuals with established T2D and/or obesity. The reversal of vascular RCE has been observed after administration of the sodium-glucose cotransporter-2 inhibitor (SGLT2i), empagliflozin, or after bariatric surgery for severe obesity. In this review, we explore emerging evidence that links improved dysglycemia to a reduction in systemic oxidative stress and recovery of circulating pro-vascular progenitor cell content required for blood vessel repair. Given that bariatric surgery consistently increases systemic glucagon-like-peptide 1 (GLP-1) release, we also focus on evidence that the use of GLP-1 receptor agonists (GLP-1RA) during obesity may act to inhibit the progression of systemic dysglycemia and adiposity, and indirectly reduce inflammation and oxidative stress, thereby limiting the impact of RCE. Therefore, therapeutic intervention with currently-available GLP-1RA may provide a less-invasive modality to reverse RCE, bolster vascular repair mechanisms, and improve cardiometabolic risk in individuals living with T2D and obesity.
Assuntos
Cirurgia Bariátrica , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Doenças Cardiovasculares/prevenção & controle , Doença Crônica , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/cirurgia , Peptídeo 1 Semelhante ao Glucagon , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
The examination of circulating pro-vascular progenitor cell frequency and function is integral in understanding aberrant blood vessel homeostasis in individuals with cardiometabolic disease. Here, we outline the characterization of progenitor cell subsets from peripheral blood using high aldehyde dehydrogenase (ALDH) activity, an intracellular detoxification enzyme previously associated with pro-vascular progenitor cell status. Using this protocol, cells can be examined by flow cytometry for ALDH activity and lineage restricted cell surface markers simultaneously. For complete details on the use and execution of this protocol, please refer to Terenzi et al. (2019) and Hess et al. (2019, 2020).
Assuntos
Aldeído Desidrogenase/análise , Citometria de Fluxo/métodos , Células-Tronco/metabolismo , Aldeído Desidrogenase/metabolismo , Células Sanguíneas/fisiologia , Contagem de Células/métodos , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Neovascularização Fisiológica , Regeneração , Células-Tronco/citologiaRESUMO
Bariatric surgery, in addition to the benefit of sustained weight loss, can also reduce cardiometabolic risk and mortality. Lifelong vessel maintenance is integral to the prevention of cardiovascular disease. Using aldehyde dehydrogenase activity, an intracellular detoxifying enzyme present at high levels within pro-vascular progenitor cells, we observed an association between chronic obesity and "regenerative cell exhaustion" (RCE), a pathology whereby chronic assault on circulating regenerative cell types can result in adverse inflammation and diminished vessel repair. We also describe that, at 3 months following bariatric surgery, systemic inflammatory burden was reduced and pro-angiogenic macrophage precursor content was improved in subjects with severe obesity, suggesting the restoration of a microenvironment to support vessel homeostasis. These data suggest that bariatric surgery may reverse deleterious events that predispose patients with morbid obesity to cardiovascular risk.
Assuntos
Doenças Cardiovasculares/etiologia , Granulócitos/patologia , Monócitos/patologia , Obesidade Mórbida/sangue , Obesidade Mórbida/cirurgia , Adolescente , Adulto , Cirurgia Bariátrica , Contagem de Células Sanguíneas , Doenças Cardiovasculares/sangue , Estudos de Casos e Controles , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Ativação de Macrófagos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Comportamento de Redução do Risco , Redução de Peso/fisiologia , Adulto JovemRESUMO
Ischemic cardiovascular complications remain a major cause of mortality in people with type 2 diabetes (T2D). Individuals with T2D may have a reduced ability to revascularize ischemic tissues due to abnormal production of circulating provascular progenitor cells. This 'regenerative cell exhaustion' process is intensified by increasing oxidative stress and inflammation and during T2D progression. Chronic exhaustion may be mediated by changes in the bone marrow microenvironment that dysregulate the wingless related integration site network, a central pathway maintaining the progenitor cell pool. Restoration of vascular regenerative cell production by reducing glucotoxicity with contemporary antihyperglycemic agents, by reducing systemic inflammation postbariatric surgery, or by modulating progenitor cell provascular functions using exosomal manipulation, may provide unique approaches for mitigating ischemic disease.
Assuntos
Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Suscetibilidade a Doenças , Neovascularização Fisiológica , Animais , Biomarcadores , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Medula Óssea , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Fenômenos Fisiológicos Cardiovasculares , Diferenciação Celular , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/terapia , Vesículas Extracelulares/metabolismo , Humanos , Obesidade/metabolismo , Obesidade/cirurgia , Estresse Oxidativo , Risco , Transdução de Sinais , Nicho de Células-Tronco , Pesquisa Translacional BiomédicaRESUMO
Hess et al. quantified circulating aldehyde dehydrogenase-expressing (ALDHhi) cell subsets in people with T2DM given either empagliflozin (EMPA) or placebo. EMPA treatment increased circulating pro-angiogenic CD133+ progenitor cells, decreased pro-inflammatory ALDHhi granulocyte precursors, and increased ALDHhi monocytes with M2 polarization. EMPA treatment improved T2DM-associated "regenerative cell depletion" contributing to enhanced vascular health.