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.
BackgroundDiabetic bladder dysfunction (DBD) encompasses a broad spectrum of complications that affect over 50% of individuals with diabetes mellitus. While symptoms can greatly affect these individuals' quality of life, there are currently no targeted therapies available. Our focus is the early compensated phase, characterized by symptoms of urinary urgency and overactive bladder. Recent studies have shown that lysine acetylation, a post‐translational modification, may be associated with diabetic complications. We hypothesized that changes in acetyltransferase regulation result in increased lysine acetylation in bladder tissue, which in turn contribute to the pathogenesis of DBD.Materials and MethodsAdult male Wistar rats were randomized into two experimental groups. The diabetic group received a single intraperitoneal injection of 65 mg/kg of STZ in 0.01 M Sodium Citrate. Diabetes was confirmed with fasting glucose levels greater than 150 mg/dL. The control group received an equal volume of vehicle via intraperitoneal injection. 6 weeks post‐injection, DBD was confirmed with void spot assay. Rats were euthanized under isoflurane (via nasal in 100% O2) and the bladders were removed for molecular and histological analysis. Blood samples were collected for biochemical analysis.ResultsDiabetic animals showed higher levels of fasting glucose (433.5 ± 28.7 vs. 90.43 ± 1.36 mg/dL control, p<0.02, n=15), and decreased body weight (516.6 ± 18.8 vs. 376.1 ± 18.1 grams control, p<0.001, n=15). Diabetic animals also exhibited lipid profile changes, including increased triglycerides (522.7 ± 55.4 vs. 68.03 ± 11.7 mg/dL control, p<0.0002, n=10) and increased free fatty acids (0.663 ± 0.047 vs. 0.433 ± 0.034 mM control, p<0.005, n=13). Diabetic animals also showed increased bladder weight (0.2006 ± 0.0189 vs. 0.1344 ± 0.0557 grams control, p<0.015, n=8). Void spot assays confirmed an increase in overall voiding volume in diabetic rats (62.22 ± 12.2 vs. 6.198 ± 2.62 % of paper with urine control, p<0.01, n=10). Histological analysis showed detrusor hypertrophy in diabetic animals (1465.17 ± 62.92 vs. 1073.92 ± 125.84 μm control, p<0.0001). Global lysine acetylation was increased in experimental bladder tissue (55% in comparison to controls, p<0.005). A 90% decrease in HDAC7 expression was detected in diabetic rats compared to controls (p<0.0001, n=12).ConclusionOur findings suggest that downregulation of HDAC7 associated with hyperacetylation of diabetic bladder tissue indicates a potential therapeutic target for DBD. Using molecular and pharmacological approaches to overexpress HDAC7, we will confirm its role in DBD etiology. These molecular insights will improve our understanding of this complex condition, leading to the development of targeted interventions for the early phases of DBD.Support or Funding InformationIn‐house Grant NYITThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Consumption of a western diet (WD) is a major part of modern life contributing to the epidemic of Metabolic Syndrome (MS), a significant risk factor for cardiovascular disease. Recent studies from our laboratory have characterized a model of WD induced MS in female rats. Adopting a healthier diet may be sufficient to reverse the constellation of metabolic symptoms associated with MS including obesity-related hypertension. However, it remains unclear if returning to a normal diet overcomes cardiovascular dysfunction associated with MS. We hypothesized that cardiovascular dysfunction will persist despite diet reversal due to altered PPAR-γ, an important vascular tone regulator, in the perivascular adipose tissue (PVAT). Eight-week old female Wistar rats were fed a WD (21% fat, 50% carbohydrate (34% sucrose) for 20 weeks (WD group) to induce MS. Then, the rats were subjected to diet reversal for 8 weeks (rWD group). The control group received a regular chow diet (5% fat, 48.7% carbohydrate (3.2% sucrose). WD group exhibited increased body weight, triglyceride levels, intolerance to glucose and systolic blood pressure characterizing MS. Direct measurement of blood pressure via right carotid catheterization showed that WD increased systolic blood pressure (141.61 ± 10 vs. 119.52 ± 9 mmHg) compared with controls. Strikingly, diet reversal was unable to drop systolic blood pressure (139.87 ± 13 mmHg). WD impaired acetylcholine and sodium nitroprusside-mediated relaxation in aortic rings. These effects remained unchanged even after diet reversal. Expression of PPAR-γ in aortic PVAT was significantly reduced in the WD group (3.2 fold) and in the rWD group (2.4 fold ) compared with controls. Moreover, we found high levels of lysine acetylation in the PVAT from WD (2.8 fold ) and rWD group (2.0 fold) compared with controls. Despite reversal WD led to significant improvement of all metabolic parameters, including weight loss, this strategy was unable to reverse vascular dysfunction and elevated blood pressure caused by WD consumption. Decreased PPAR-γ expression in PVAT associated with hyperacetylation will be further examined as a potential mechanism underlying persistent vascular dysfunction in WD-induced MS.
Background Overconsumption of a Western Diet (WD), characterized by high‐fat and high sugar, frequently results in obesity‐related hypertension. During obesity, PVAT switches from a vasculo‐protective to an inflammatory phenotype contributing to vascular dysfunction and hypertension. The transcriptional repressor B‐Cell Lymphoma 6 (BCL6) has recently emerged as a negative regulator of adiposity. However, whether obesity alters BCL6 levels in the PVAT remains unknown. We hypothesized that WD upregulates BCL6 in PVAT resulting in dysfunctional PVAT‐induced hypertension. Methods Recently, our lab established a model of WD‐induced obesity in female rats. Eight‐week‐old female Wistar rats were randomized into two experimental groups: Control group (n=6) received a regular chow diet (5% fat, 48.7% carbohydrate [3.2% sucrose], 24.1% protein) while the WD group (n=7) received a WD (21% fat, 50% carbohydrate [34% sucrose], 20% protein), for 20 weeks. Cardiovascular parameters, including direct blood pressure and endothelium‐independent vasodilation measurements, were assessed by carotid catheterization and cumulative concentration curve for sodium nitroprusside (SNP) by using a wire myography, respectively. Metabolic parameters were obtained by biochemical assays and homeostatic model of insulin resistance (HOMA‐IR) calculation. At terminal experiments, thoracic aorta and PVAT were collected for molecular and histological analysis. Results As expected, the WD group exhibited exacerbated cardiometabolic alterations including increased body weight (412 ± 22 vs. 299 ± 5 g, p<0.01), serum triglycerides (184.2±7.44 vs. 51.5±4.9 mg/dl, p<0.001), nonesterified free fatty acid (0.98±0.05 vs. 0.05±0.02 mM, p<0.05) and insulin resistance (HOMA‐IR: 10.22 ± 1.45 vs. 1.43 ± 0.03 a.u, p<0.05), compared to controls. WD caused an increase in systolic blood pressure (147.3±7 vs. 122.7±5.29 mmHg controls, p<0.01), along with increased heart rate (381.91±11 vs. 334.26±22 bpm controls, p<0.05). SNP‐induced relaxation in aortas was reduced in the WD group (Emax: 78.55±4% vs. 96.88±6% controls, p<0.01), indicating that the decreased vasodilation caused by a WD involves vascular smooth muscle cell dysfunction. More importantly, these vascular complications were directly associated with robust phenotypic changes in aortic PVAT, which included switches from a brown‐like to a white‐like adipose tissue as evidenced by enlarged adipocytes, 60% reduction on mitochondrial density (p<0.01) and increased expression of inflammatory marker MCP‐1 (2.5‐fold increased, p<0.001) compared to controls. Strikingly, BCL6 expression was markedly elevated in PVAT from the WD group (2.1‐fold increased, p<0.05). Conclusion Our results show for the first time that BCL6 is upregulated in the aortic PVAT under obesogenic conditions. BCL6 has the potential to be a therapeutic target for obesity‐associated vascular dysfunction and hypertension. Support or Funding Information NIH
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