Hess David A, Verma Subodh, Bhatt Deepak, Bakbak Ehab, Terenzi Daniella C, Puar Pankaj, Cosentino Francesco
Department of Pharmacology and Toxicology, University of Toronto, 27 King's College Circle, Toronto, ON M5S 3J3, Canada.
Division of Vascular Surgery, St. Michael's Hospital, 30 Bond Street, Toronto, ON M5B 1W8, Canada.
Eur Heart J. 2022 Feb 10;43(6):450-459. doi: 10.1093/eurheartj/ehab758.
Chronic cardiometabolic assaults during type 2 diabetes (T2D) and obesity induce a progenitor cell imbalance in the circulation characterized by overproduction and release of pro-inflammatory monocytes and granulocytes from the bone marrow alongside aberrant differentiation and mobilization of pro-vascular progenitor cells that generate downstream progeny for the coordination of blood vessel repair. This imbalance can be detected in the peripheral blood of individuals with established T2D and severe obesity using multiparametric flow cytometry analyses to discern pro-inflammatory vs. pro-angiogenic progenitor cell subsets identified by high aldehyde dehydrogenase activity, a conserved progenitor cell protective function, combined with lineage-restricted cell surface marker analyses. Recent evidence suggests that progenitor cell imbalance can be reversed by treatment with pharmacological agents or surgical interventions that reduce hyperglycaemia or excess adiposity. In this state-of-the-art review, we present current strategies to assess the progression of pro-vascular regenerative cell depletion in peripheral blood samples of individuals with T2D and obesity and we summarize novel clinical data that intervention using sodium-glucose co-transporter 2 inhibition or gastric bypass surgery can efficiently restore cell-mediated vascular repair mechanisms associated with profound cardiovascular benefits in recent outcome trials. Collectively, this thesis generates a compelling argument for early intervention using current pharmacological agents to prevent or restore imbalanced circulating progenitor content and maintain vascular regenerative cell trafficking to sites of ischaemic damage. This conceptual advancement may lead to the design of novel therapeutic approaches to prevent or reverse the devastating cardiovascular comorbidities currently associated with T2D and obesity.
2型糖尿病（T2D）和肥胖症期间的慢性心脏代谢攻击会导致循环系统中祖细胞失衡，其特征是骨髓中促炎单核细胞和粒细胞过度产生和释放，同时促血管祖细胞异常分化和动员，这些祖细胞产生下游子代以协调血管修复。使用多参数流式细胞术分析可以在已确诊的T2D和严重肥胖个体的外周血中检测到这种失衡，以区分由高醛脱氢酶活性（一种保守的祖细胞保护功能）确定的促炎与促血管生成祖细胞亚群，并结合谱系限制性细胞表面标志物分析。最近的证据表明，通过使用降低高血糖或减少肥胖的药物治疗或手术干预，可以逆转祖细胞失衡。在这篇最新综述中，我们介绍了评估T2D和肥胖个体外周血样本中促血管再生细胞耗竭进展的当前策略，并总结了新的临床数据，即在最近的结果试验中，使用钠-葡萄糖协同转运蛋白2抑制剂或胃旁路手术进行干预可以有效恢复细胞介导的血管修复机制，并带来显著的心血管益处。总的来说，本论文提出了一个令人信服的观点，即使用当前的药物进行早期干预，以预防或恢复循环祖细胞含量失衡，并维持血管再生细胞向缺血损伤部位的运输。这一概念上的进展可能会导致设计新的治疗方法，以预防或逆转目前与T2D和肥胖相关的毁灭性心血管合并症。
