Carrillo-Sepulveda Maria Alicia, Maddie Nicole, Johnson Christina Mary, Burke Cameron, Lutz Osina, Yakoub Bamwa, Kramer Benjamin, Persand Dhandevi
Department of Biomedical Sciences, College of Osteopathic Medicine, New York Institute of Technology, Northern Blvd., Old Westbury, NY, 11568, USA.
Department of Life Sciences, College of Arts and Sciences, New York Institute of Technology, Northern Blvd., Old Westbury, NY, 11568, USA.
Mol Med. 2022 Mar 8;28(1):30. doi: 10.1186/s10020-022-00441-4.
Advanced type 2 diabetes mellitus (T2DM) accelerates vascular smooth muscle cell (VSMC) dysfunction which contributes to the development of vasculopathy, associated with the highest degree of morbidity of T2DM. Lysine acetylation, a post-translational modification (PTM), has been associated with metabolic diseases and its complications. Whether levels of global lysine acetylation are altered in vasculature from advanced T2DM remains undetermined. We hypothesized that VSMC undergoes dysregulation in advanced T2DM which is associated with vascular hyperacetylation.
Aged male Goto Kakizaki (GK) rats, a non-obese murine model of T2DM, and age-matched male Wistar rats (control group) were used in this study. Thoracic aortas were isolated and examined for measurement of global levels of lysine acetylation, and vascular reactivity studies were conducted using a wire myograph. Direct arterial blood pressure was assessed by carotid catheterization. Cultured human VSMCs were used to investigate whether lysine acetylation participates in high glucose-induced reactive oxygen species (ROS), a crucial factor triggering diabetic vascular dysfunction.
The GK rats exhibited marked glucose intolerance as well as insulin resistance. Cardiovascular complications in GK rats were confirmed by elevated arterial blood pressure and reduced VSMC-dependent vasorelaxation. These complications were correlated with high levels of vascular global lysine acetylation. Human VSMC cultures incubated under high glucose conditions displayed elevated ROS levels and increased global lysine acetylation. Inhibition of hyperacetylation by garcinol, a lysine acetyltransferase and p300/CBP association factor (PCAF) inhibitor, reduced high glucose-induced ROS production in VSMC.
This study provides evidence that vascular hyperacetylation is associated with VSMC dysfunction in advanced T2DM. Understanding lysine acetylation regulation in blood vessels from diabetics may provide insight into the mechanisms of diabetic vascular dysfunction, and opportunities for novel therapeutic approaches to treat diabetic vascular complications.
晚期2型糖尿病（T2DM）会加速血管平滑肌细胞（VSMC）功能障碍，这会导致血管病变的发展，而血管病变与T2DM的最高发病率相关。赖氨酸乙酰化作为一种翻译后修饰（PTM），已与代谢性疾病及其并发症相关联。晚期T2DM患者血管中整体赖氨酸乙酰化水平是否发生改变仍未确定。我们推测晚期T2DM中VSMC会发生失调，这与血管高乙酰化有关。
本研究使用了老年雄性Goto Kakizaki（GK）大鼠（一种非肥胖型T2DM小鼠模型）和年龄匹配的雄性Wistar大鼠（对照组）。分离胸主动脉并检测整体赖氨酸乙酰化水平，使用线肌动描记器进行血管反应性研究。通过颈动脉插管评估直接动脉血压。使用培养的人VSMC来研究赖氨酸乙酰化是否参与高糖诱导的活性氧（ROS）生成，ROS是引发糖尿病血管功能障碍的关键因素。
GK大鼠表现出明显的葡萄糖不耐受以及胰岛素抵抗。动脉血压升高和VSMC依赖性血管舒张功能降低证实了GK大鼠存在心血管并发症。这些并发症与血管整体赖氨酸乙酰化水平升高相关。在高糖条件下培养的人VSMC显示ROS水平升高且整体赖氨酸乙酰化增加。藤黄菌素（一种赖氨酸乙酰转移酶和p300/CBP相关因子（PCAF）抑制剂）对高乙酰化的抑制作用降低了VSMC中高糖诱导的ROS生成。
本研究提供了证据表明血管高乙酰化与晚期T2DM中的VSMC功能障碍相关。了解糖尿病患者血管中赖氨酸乙酰化调节可能有助于深入了解糖尿病血管功能障碍的机制，并为治疗糖尿病血管并发症提供新的治疗方法。
