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.
Obesity-related cardiovascular complications are a major health problem worldwide. Overconsumption of the Western diet is a well-known culprit for the development of obesity. While short-term weight loss through switching from a Western diet to a normal diet is known to promote metabolic improvement, its short-term effects on vascular parameters are not well-characterized. Glucagon-like peptide 1 (GLP-1), an incretin with vasculo-protective properties, is decreased in plasma from obese patients. We hypothesize that obesity causes persistent vascular dysfunction in association with downregulation of vascular GLP-1R. Female Wistar rats were randomized into three groups: lean received a chow diet for 28 weeks, obese received a Western diet for 28 weeks, and reverse obese received a Western diet for 18 weeks followed by 12 weeks of standard chow diet. The obese group exhibited increased body weight and body mass index, while the reverse obese group lost weight. Weight loss failed to reverse impaired vasodilation and high systolic blood pressure in obese rats. Strikingly, our results show that obese rats exhibit decreased serum levels of GLP-1 accompanied by decreased vascular GLP-1R expression. Weight loss recovered GLP-1 serum levels, however GLP-1R expression remained downregulated. Decreased Akt phosphorylation was observed in the obese and reverse obese group, suggesting that GLP-1/Akt signaling is persistently downregulated. Our results support that GLP-1 signaling is associated with obesity-related vascular dysfunction in females and short-term weight loss does not guarantee recovery of vascular function. This study suggests that GLP-1R may be a potential target for therapeutic intervention in obesity-related hypertension in females.
Heart failure results in significant morbidity and mortality. Heart failure with reduced ejection fraction (HfrEF) in the absence of atrial fibrillation has been increasingly considered an independent risk factor for ischemic stroke, partly because of the development of left ventricular thrombus and subsequent cardioembolic stroke and partly because of hemodynamic impairment. Here, we present a case of a 60-yearold male with heart failure with reduced ejection fraction, who presented with cardioembolic ischemic stroke. In the investigation to localize the source, he was found to have slow intra-ventricular blood flow, which over shorter periods of follow up lead to the development of left ventricle intra-mural thrombi. Meanwhile, the patient also developed hemorrhagic conversion in the ischemic stroke, which further complicated the choice of anticoagulation. To date, no consensus has been developed on the choice of anticoagulation and clinical criteria for the use of anticoagulation in patients having HfrEF and sinus rhythm. This case brings forth a need for further research on whether anticoagulation would be beneficial in patients with HfrEF and sinus rhythm.
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.
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