R. Garrett Morgan

TNF-α impairs endothelial function in adipose tissue resistance arteries of mice with diet-induced obesity

We tested the hypothesis that high fat (HF) feeding results in endothelial dysfunction in resistance arteries of epididymal white adipose tissue (eWAT) and is mediated by adipose tissue inflammation. When compared with normal chow (NC)-fed mice (n = 17), HF-fed male B6D2F1 mice were glucose intolerant and insulin resistant as assessed by glucose tolerance test (area under the curve; HF, 18,174 ± 1,889 vs. NC, 15,814 ± 666 mg·dl(-1)·min(-1); P < 0.05) and the homeostatic model assessment (HF, 64.1 ± 4.3 vs. NC, 85.7 ± 6.4; P = 0.05). HF diet-induced metabolic dysfunction was concomitant with a proinflammatory eWAT phenotype characterized by greater macrophage infiltration (HF, 3.9 ± 0.8 vs. NC, 0.8 ± 0.4%; P = 0.01) and TNF-α (HF, 22.6 ± 4.3 vs. NC, 11.4 ± 2.5 pg/dl; P < 0.05) and was associated with resistance artery dysfunction, evidenced by impaired endothelium-dependent dilation (EDD) (maximal dilation; HF, 49.2 ± 10.7 vs. NC, 92.4 ± 1.4%; P < 0.01). Inhibition of nitric oxide (NO) synthase by N(ω)-nitro-L-arginine methyl ester (L-NAME) reduced dilation in NC (28.9 ± 6.3%; P < 0.01)- and tended to reduce dilation in HF (29.8 ± 9.9%; P = 0.07)-fed mice, eliminating the differences in eWAT artery EDD between NC- and HF-fed mice, indicative of reduced NO bioavailability in eWAT resistance arteries after HF feeding. In vitro treatment of excised eWAT arteries with recombinant TNF-α (rTNF) impaired EDD (P < 0.01) in NC (59.7 ± 10.9%)- but not HF (59.0 ± 9.3%)-fed mice. L-NAME reduced EDD in rTNF-treated arteries from both NC (21.9 ± 6.4%)- and HF (29.1 ± 9.2%)-fed mice (both P < 0.01). In vitro treatment of arteries with a neutralizing antibody against TNF-α (abTNF) improved EDD in HF (88.2 ± 4.6%; P = 0.05)-fed mice but was without effect on maximal dilation in NC (89.0 ± 5.1%)-fed mice. L-NAME reduced EDD in abTNF-treated arteries from both NC (25.4 ± 7.5%)- and HF (27.1 ± 16.8%)-fed mice (both P < 0.01). These results demonstrate that inflammation in the visceral adipose tissue resulting from diet-induced obesity impairs endothelial function and NO bioavailability in the associated resistance arteries. This dysfunction may have important implications for adipose tissue blood flow and appropriate tissue function.

α1-Adrenergic Responsiveness in Human Skeletal Muscle Feed Arteries: The Impact of Reducing Extracellular PH

•  What is the central question of this study? In human arteries involved in the regulation of muscle blood flow, there is a lack of data about whether acidosis alters vascular sensitivity to vasoactive agents, as well as altering endothelium dependent vasorelaxation. Little is known about the interaction of metabolites and vascular function in human skeletal muscle feed arteries. •  What is the main finding and its importance? Increasing acidosis attenuated the response and sensitivity of the arteries to phenylephrine; this effect was selective to the receptor over smooth muscle. Acidosis did not alter endothelium dependent vasorelaxation. Impaired vasoconstriction coupled with intact vasorelaxation, promotes decreased vascular tone with exposure to acidosis, and may contribute to sympatholysis during exercise.

The impact of ageing on adipose structure, function and vasculature in the B6D2F1 mouse: evidence of significant multisystem dysfunction

Dysfunction in the adipose tissue, characterized by reduced adipocyte size, tissue fibrosis and ectopic lipid accumulation, has been implicated in age‐associated metabolic dysfunction, but it is not known how ageing affects the function of the arteries and mitochondria within the adipose tissue. Mitochondrial lipid utilization is impaired in adipose tissue of old mice, evidenced by reduced substrate control ratios in the presence of lipid substrates and is concomitant with increased oxidative stress. Ageing leads to endothelial dysfunction, evidenced by reduced endothelium‐dependent dilation in resistance arteries, reduced angiogenic capacity and reduced vascularity of the adipose tissue. These results indicate that arterial and mitochondrial dysfunction accompany age‐associated adipose tissue and systemic metabolic dysfunction and suggest that targeting arterial or mitochondrial function to improve adipose tissue function may have important application in the treatment of age‐associated metabolic dysfunction.

Greater impairments in cerebral artery compared with skeletal muscle feed artery endothelial function in a mouse model of increased large artery stiffness.

Increased large artery stiffness is a hallmark of arterial dysfunction with advancing age and is also present in other disease conditions such as diabetes. Increased large artery stiffness is correlated with resistance artery dysfunction in humans. Using a mouse model of altered arterial elastin content, this is the first study to examine the cause‐and‐effect relationship between large artery stiffness and peripheral resistance artery function. Our results indicate that mice with genetically greater large artery stiffness have impaired cerebral artery endothelial function, but generally preserved skeletal muscle feed artery endothelial function. The mechanisms for impaired cerebral artery endothelial function are reduced nitric oxide bioavailability and increased oxidative stress. These findings suggest that interventions that target large artery stiffness may be important to reduce disease risk associated with cerebral artery dysfunction in conditions such as advancing age.

Relative contributions of severe dopaminergic neuron ablation and dopamine depletion to cognitive impairment

Parkinsons disease (PD) is characterized by the loss of dopaminergic neurons and produces a movement disorder and cognitive impairment that becomes more extensive with the duration of the disease. To what extent cognitive impairment in advanced PD can be attributed to severe loss of dopamine (DA) signaling is not well understood. Furthermore, it is unclear if the loss of DA neurons contributes to the cognitive impairment caused by the reduction in DA signaling. We generated genetic mouse models with equally severe chronic loss of DA achieved by either extensive ablation of DA neurons or inactivation of DA synthesis from preserved neurons and compared their motor and cognitive performance. Motor behaviors were equally blunted in both models, but we observed that DA neuron ablation caused more severe cognitive deficits than DA depletion. Both models had marked deficits in cue-discrimination learning. Yet, deficits in cue-discrimination learning were more severe in mice with DA neuron ablation and only mice with DA neuron ablation had drastically impaired performance in spatial learning, spatial memory and object memory tests. These results indicate that while a severe reduction in DA signaling results in motor and cognitive impairments, the loss of DA neurons promotes more extensive cognitive deficits and suggest that a loss of additional factors that depend on DA neurons may participate in the progressive cognitive decline found in patients with PD.

Age-Associated ALU Element Instability in White Blood Cells Is Linked to Lower Survival in Elderly Adults: A Preliminary Cohort Study.

Background ALU element instability could contribute to gene function variance in aging, and may partly explain variation in human lifespan. Objective To assess the role of ALU element instability in human aging and the potential efficacy of ALU element content as a marker of biological aging and survival. Design Preliminary cohort study. Methods We measured two high frequency ALU element subfamilies, ALU-J and ALU-Sx, by a single qPCR assay and compared ALU-J/Sx content in white blood cell (WBCs) and skeletal muscle cell (SMCs) biopsies from twenty-three elderly adults with sixteen healthy sex-balanced young adults; all-cause survival rates of elderly adults predicted by ALU-J/Sx content in both tissues; and cardiovascular disease (CVD)- and cancer-specific survival rates of elderly adults predicted by ALU-J/Sx content in both tissues, as planned subgroup analyses. Results We found greater ALU-J/Sx content variance in WBCs from elderly adults than young adults (P < 0.001) with no difference in SMCs (P = 0.94). Elderly adults with low WBC ALU-J/Sx content had worse four-year all-cause and CVD-associated survival than those with high ALU-J/Sx content (both P = 0.03 and hazard ratios (HR) ≥ 3.40), while WBC ALU-J/Sx content had no influence on cancer-associated survival (P = 0.42 and HR = 0.74). SMC ALU-J/Sx content had no influence on all-cause, CVD- or cancer -associated survival (all P ≥ 0.26; HR ≤ 2.07). Conclusions These initial findings demonstrate that ALU element instability occurs with advanced age in WBCs, but not SMCs, and imparts greater risk of all-cause mortality that is likely driven by an increased risk for CVD and not cancer.

Experimental reduction of miR-92a mimics arterial aging

MicroRNAs (miRs) are small non-coding RNAs that are important regulators of aging and cardiovascular diseases. MiR-92a is important in developmental vascular growth and tumorigenesis and two of its putative targets, tumor necrosis factor alpha receptor 1 (TNFR1) and collagen type 1, play a role in age-related arterial dysfunction. We hypothesized that reduced miR-92a expression contributes to age-related arterial dysfunction characterized by endothelial dysfunction and increased large artery stiffness. MiR-92a is reduced 39% (RT-PCR, p<0.05) in arteries of older adults compared to young adults. Similarly, there was a 40% reduction in miR-92a in aortas of old (29months, n=13) compared to young (6months, n=11) B6D2F1 mice, an established model of vascular aging. To determine if reduced miR-92a contributes to arterial dysfunction; miR-92a was inhibited in vivo in young mice using antagomirs (I.P., 4wks). Antagomir treatment was associated with a concomitant 48% increase in TNFR1 (Western blot, p<0.05), 19% increase in type 1 collagen (immunohistochemistry, p<0.01), and a reduction in endothelial dependent dilation (max dilation: 93±1 vs. 73±5%, p<0.01) in response to acetylcholine (ACh, 10(-9) to 10(-4)M). Treatment with the nitric oxide (NO) synthase inhibitor, L-NAME (10(-4)M), revealed that impaired ACh dilation after antagomir treatment resulted from reduced NO bioavailability. Inhibition of miR-92a also increased arterial stiffness (pulse wave velocity, 309±13 vs. 484±52cm/s, p<0.05). Together, these results suggest that experimental reductions in arterial miR-92a partially mimic the arterial aging phenotype and we speculate that modulating miR-92a may provide a therapeutic strategy to improve age-related arterial dysfunction.

Network Mendelian Randomization Study Design to Assess Factors Mediating the Causal Link Between Telomere Length and Heart Disease.

Mendelian randomization study designs represent new powerful tools available to researchers that enable causal inferences to be made about the effects of risk factors in health and disease outcomes in the context of a prospective observational study.1–4 These study designs involve estimating the association between a genetically modifiable risk factor and health and disease outcomes.1,2 If individuals with genetically lower or higher levels of a risk factor of interest are at greater or lesser risk of an outcome, then it can be inferred that the risk factor has a causal relationship to that outcome.2–4 Provided that a chosen genetic variant is strongly associated with the risk factor of interest, is not associated with other factors that might affect the risk factor, and imparts its influence on a given outcome exclusively through its link to the risk factor, these causal inferences are considered to be robust.2,3 Mendelian randomization study designs have become increasingly popular among epidemiologists in recent years as recently completed genome-wide association and genome sequencing studies have substantially increased our knowledge of the genetic factors associated with health and disease.1 Using Mendelian randomization techniques allows researchers to conduct studies that can make the kind of causal inferences that are typically only attainable from randomized controlled trials, thus avoiding much of expense, difficulty, and ethical issues that often arise with such trials.1,2,4 Furthermore, as demonstrated in an exciting recent publication in Circulation Research , titled Exploring the Causal Pathway from Telomere Length to Coronary Heart Disease: A Network Mendelian Randomization Study by Zhan et al,5 these study designs allow assessment of the influence of risk factors that are impossible to manipulate in humans, like telomere length, on disease outcomes and the …