Vascular dysfunction associated with hypertension comprises hypercontractility and impaired vasodilation. We have previously demonstrated that triiodothyronine (T3), the active form of thyroid hormone, has vasodilatory effects acting through rapid onset mechanisms. In the present study, we examined whether T3 mitigates vascular dysfunction associated with hypertension. To test the direct effects of T3 in hypertensive vessels, aortas from female Dahl salt-sensitive (Dahl SS) rats fed a high-salt diet (8% NaCl, HS group) and their age-matched controls fed a standard low-salt diet (0.3% NaCl, LS group) for 16 weeks were isolated and used in ex vivo vascular reactivity studies. We confirmed that the HS group exhibited a higher systolic blood pressure in comparison with the control LS group and displayed aortic remodeling. Aortas from both groups were pretreated with T3 (0.1 mM) for 30 minutes at 37°C in a 5% CO 2 incubator before functional vascular studies. T3 treatment significantly attenuated hypercontractility and improved impaired endothelium-dependent vasodilation in aortas from the HS group. These vascular improvements in response to T3 were accompanied by increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at serine 239, a vasodilatory factor of the cGMP-dependent protein kinase (PKG)/ VASP signaling pathway in vascular smooth muscle cells. Moreover, increased production of reactive oxygen species in aortas from the HS group were significantly reduced by T3, suggesting a potential antioxidant effect of T3 in the vasculature. These results demonstrate that T3 can mitigate hypertension-related vascular dysfunction through the VASP signaling pathway and by reducing vascular ROS production. SIGNIFICANCE STATEMENT This study demonstrates that triiodothyronine (T3) directly acts on vascular tone and has a beneficial effect in hypertensioninduced vascular dysfunction. T3 augmented vasodilation and diminished vasoconstriction in blood vessels from hypertensive rats in association with activation of the protein kinase G/vasodilator-stimulated phosphoprotein signaling pathway that activates vascular relaxation and exerted an antioxidant effect. Collectively, these results show that T3 is a potential vasoprotective agent with rapid action on hypertensionrelated vascular dysfunction.

Background 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. Methods 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. Results 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. Conclusion 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.

Obesity is a major risk factor for hypertension. Obesity-related hypertension impacts more women than men, but the underlying mechanisms remain unclear. GLP-1, an incretin released after food intake, exerts vasculo-protective effects. Human studies have shown that GLP-1 levels are decreased in obese patients. We hypothesized that vascular GLP-1 signaling is reduced in obesity and weight loss rescues this signaling. Eight-week-old female Wistar rats were randomized into three groups: LEAN (n=9) received a chow diet (5% fat, 48.7% carbohydrate [3.2% sucrose], 24.1% protein) for 28 weeks, OBESE (n=7) received a Western diet (21% fat, 50% carbohydrate [34% sucrose], 20% protein) for 28 weeks, and reverse obese (rOBESE) (n=7) received a Western diet for 18 weeks followed by 12 weeks of chow diet. The OBESE group exhibited increased body weight (395.6 vs. 285.4g LEAN, p<0.0001) and body mass index (6.8 vs. 5.1kg/m 2 LEAN, p<0.01), while the rOBESE group lost weight (337.0 vs. 395.6g OBESE, p<0.01). Direct measurement of blood pressure (BP) using a pressure-volume catheter inserted in the carotid artery revealed increased systolic (142.8 vs. 117.2mmHg LEAN, p<0.001), diastolic (125.0 vs. 92.7mmHg LEAN, p<0.001), and mean arterial BP (130.9 vs. 107.9mmHg LEAN, p<0.001) in the OBESE group. The rOBESE group sustained elevated systolic BP (139.1 vs.117.2mmHg LEAN, p<0.05). Endothelium-dependent vasodilation studies assessed by wire myograph demonstrated that the OBESE group exhibited impaired response to acetylcholine (Emax: 82.7% vs. 97.9% LEAN, p<0.001). Similar vascular impairment was observed in the rOBESE group (EMax: 81.3% vs 97.9% LEAN, p<0.001). Strikingly, while decreased GLP-1 serum levels in the OBESE group (10.6 vs. 18.4pM/mL LEAN, p<0.05) returned to normal levels in the rOBESE group (19.4 vs.18.4pM/mL LEAN), GLP-1 receptor protein expression was reduced in both groups (24% decrease in OBESE, 52% decrease in rOBESE) as compared to LEAN. Our results support that GLP-1 signaling is implicated in obesity-related vascular dysfunction in females and weight loss does not guarantee recovery of protective GLP-1 signaling nor improvement of vasodilation. Conclusion: GLP-1 is a potential therapeutic target for obesity-related hypertension in females.

Background Obesity frequently leads to non‐alcoholic fatty liver disease (NAFLD), the most common liver problem affecting the American population. In fact, the prevalence of NAFLD in adult Americans ranges from 25‐46%. To date, there is no specific treatment for NAFLD. In severe cases, NAFLD can lead to fibrosis and cirrhosis which evolves into nonalcoholic steatohepatitis (NASH). Most patients with NAFLD experience no symptoms, making it a silent killer. Evidence has suggested that Toll‐like receptor 4 (TLR4) signaling, a key component of innate immunity, is implicated in the pathogenesis of NAFLD; however, the mechanisms of TLR4 activation remain unclear. We hypothesized that hyperacetylation of TLR4 leads to its overactivation in obesity, contributing to NAFLD development. Methods Eight‐week‐old male C57BL/6 mice were randomized into two experimental groups: the control group (n=4) received a regular chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose], 24.1% protein) and the Western diet (WD) group (n=4) received a WD (21% fat, 50% carbohydrates [34% sucrose], and 20% protein) for 36 weeks. Body weight was obtained and intraperitoneal glucose tolerance test (IPGTT) was performed over the course of the dietary protocol at weekly and monthly intervals, respectively. During terminal experiments, liver tissue was isolated and processed for cross‐section histology. Staining with H&E and Oil‐Red‐O were used for grading of liver injury with the NAFLD Score, which involves summation of steatosis (0–3), lobular inflammation (0–3), and hepatocellular ballooning (0–2) scores. A final score of 0–2 indicates no NASH, 3–4 indicates borderline NASH, and 5–8 indicates NASH. TLR4 and its downstream protein expression was detected by western blot and immunoprecipitation was utilized to determine the acetylation levels of TLR4. Results The WD group exhibited increased body weight (41.22 ± 7.71 g vs 29.94 ± 1.16 g controls, p<0.05) and liver weight (1.27 ± 0.0.07 g vs 1.27 ± 0.07 g controls, p<0.05). Results from IPGTT demonstrated that male mice develop early intolerance to glucose, within 8 weeks on WD. Hepatic histology showed ballooned hepatocytes, lobular inflammation, and steatosis, confirming presence of NAFLD with borderline NASH. Livers from the WD group exhibited increased TLR4 expression (1.4‐fold increase, p<0.05). Of note, this was accompanied by an increase in TLR4 signaling in WD livers as confirmed by elevated expression of the downstream signaling protein TNF receptor associated factor 6 (TRAF6) (0.8‐fold increase, p<0.05). Strikingly, immunoprecipitation assay revealed that TLR4 is hyperacetylated in the livers from the WD group. Conclusions Our results demonstrate for the first time that hepatic TLR4 is hyperacetylated in obesity‐related NAFLD. This hyperacetylation may serve as a trigger for the TLR4/TRAF6 signaling activation and may prove to be crucial to the development of NAFLD and NASH in obesity.

The novel coronavirus disease 2019 (COVID-19) has given rise to a global pandemic, as well as a multitude of long-term sequelae that continue to perplex physicians around the world, including in the United States. Among the most common and impactful long-haul symptoms experienced by survivors is COVID-19 fatigue. This review will use long COVID-19, post-acute COVID-19 syndrome (PCS), and Post-Acute Sequelae of COVID-19 (PASC) as synonymous terms to refer to the chronic symptomatology; chronic fatigue associated with PASC will be referred to as COVID-19 fatigue. While the knowledge and research on the exact pathophysiological mechanisms involved in the disease is still limited, parallels have been drawn between fatigue as a component of long COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Current studies suggest applying principles of pathophysiology, diagnosis, and treatment similar to those for ME/CFS in order to aid in managing chronic fatigue in COVID-19 survivors, particularly in the primary care setting. The osteopathic family physician can use the proposed pharmacologic agents, along with osteopathic manipulative treatment (OMT), as therapeutic modalities that can be tailored to each patient’s unique case. Nevertheless, research on proven successful treatments is still scarce. For that reason, it is essential that COVID-19 fatigue is recognized early, especially since its longitudinal impacts may be debilitating for many. This review of the available literature on COVID-19 fatigue aims to help provide quality care and lessen the disease burden experienced by patients.