Vascular Protein Lysine Acetylation: Potential Epigenetic Mechanisms Mediating Diabetic Vascular Dysfunction and Metabolic Memory
Authors: Carrillo‐Sepulveda Maria Alicia 
Published: November 2023

Diabetes mellitus (DM) has reached epidemic levels in the United States, becoming one of the major public health‐care concerns. Around 70% of diabetic patients will die due to sustained vascular disease, including atherosclerosis, hypertension and stroke. Persistent diabetic vascular complications have been observed in both experimental and clinical trials, even upon proper glycemic control. This phenomenon refers to “metabolic memory”, one of the major problems in treating diabetic patients. Recent evidence suggests that epigenetic mechanisms, such as lysine acetylation, play a role in metabolic memory. Thus, the hypothesis of this present study is that augmented vascular lysine acetylation are associated with development of diabetic vascular complications and metabolic memory. Our results revealed that intact murine aortas exposed to short‐term diabetic stimuli, such as 35mM high glucose (HG) or saturated 0.1mM free fatty acids (FFAs)‐Palmitate, displayed elevated levels of lysine acetylation (HG: 30% increase, p<0.05, n=5), (Palmitate: 55% increase, p<0.01, n=5). To further determine whether increased lysine acetylation correlates with vascular dysfunction, functional studies using wire myograph were performed. Relaxation was measured by concentration‐dependent response to acetylcholine (ACh). Aortas maintained in organ cultures with HG or Palmitate for 18 hours exhibited significant impairment of relaxation (HG: 20% reduction vs. control, p<0.01, n=6), (Palmitate: 28% reduction vs. control, p<0.05, n=5), suggesting that HG and Palmitate directly causes vascular dysfunction. Using a model of “metabolic memory” in cultured human aortic endothelial cells, we found that 24 hours stimulation with HG robustly increased NFKB expression (2.4 fold increase, p<0.01, n=4), ROS generation detected by DHE staining (2.5 fold increase, p<0.05, n=4) and levels of lysine acetylation (60% increase, p<0.01) compared with unstimulated cells. Similarly, 24 hours stimulation with Palmitate also increased NFKB expression (1.8 fold increase, p<0.01, n=4), ROS generation (3.0 fold increase, p<0.05, n=4) and lysine acetylation levels (80% increase, p<0.05). After stimulation with HG or Palmitate, cells were returned to a regular medium for 72 hours. Surprisingly, elevated levels of NFKB, ROS and lysine acetylation remained unchanged after removal of HG or Palmitate stimuli, suggesting that transient exposure to diabetic stimuli generated metabolic memory. To verify whether lysine acetylation is also altered in vivo, we utilized aortas from adult male Goto kakizaki (GK), a non‐obese model of type 2 diabetes that exhibit similar metabolic and vascular disorders to the human diabetic disease. Levels of lysine acetylation were markedly elevated in aortas from GK (55% increase vs. control, p<0.01, n=5) and correlated with increased vascular ROS (3.4 fold increase vs. control, p<0.001, n=4), inflammatory marker NFKB (2.1 fold increase vs. control) and systolic blood pressure (148±8 vs. 125±3 mmHg, p<0.05, n=6). Taken together, our results demonstrated that diabetic milieu potently increases levels of lysine acetylation in the vasculature, which is correlated with persistent vascular inflammation, oxidative stress, and thus, metabolic memory. In conclusion, these findings provide valuable insights into the etiology of diabetes‐associated vasculopathy and facilitate the development of novel strategies for diabetic vascular complications prevention

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