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The immune system comprises a complex network of specialized cells that protects against infection, eliminates cancerous cells, and regulates tissue repair, thus serving a critical role in homeostasis, health span, and life span. The subterranean-dwelling naked mole-rat (NM-R; Heterocephalus glaber) exhibits prolonged life span relative to its body size, is unusually cancer resistant, and manifests few physiological or molecular changes with advancing age. We therefore hypothesized that the immune system of NM-Rs evolved unique features that confer enhanced cancer immunosurveillance and prevent the age-associated decline in homeostasis. Using single-cell RNA-sequencing (scRNA-seq) we mapped the immune system of the NM-R and compared it to that of the short-lived, cancer-prone mouse. In contrast to the mouse, we find that the NM-R immune system is characterized by a high myeloid-to-lymphoid cell ratio that includes a novel, lipopolysaccharide (LPS)-responsive, granulocyte cell subset. Surprisingly, we also find that NM-Rs lack canonical natural killer (NK) cells. Our comparative genomics analyses support this finding, showing that the NM-R genome lacks an expanded gene family that controls NK cell function in several other species. Furthermore, we reconstructed the evolutionary history that likely led to this genomic state. The NM-R thus challenges our current understanding of mammalian immunity, favoring an atypical, myeloid-biased mode of innate immunosurveillance, which may contribute to its remarkable health span.

Hartley, Craig J., Anilkumar K. Reddy, Sridhar Madala, Baby Martin-McNulty, Ronald Vergona, Mark E. Sullivan, Meredith Halks-Miller, George E. Taffet, Lloyd H. Michael, Mark L. Entman, and YiXin Wang. Hemodynamic changes in apolipoprotein E-knockout mice. Am J Physiol Heart Circ Physiol 279: H2326-H2334, 2000.--Apolipoprotein E-knockout (ApoE-KO) mice develop advanced atherosclerotic lesions by 1 yr of age and have been well characterized pathologically and morphologically, but little is known regarding their cardiovascular physiology and hemodynamics. We used noninvasive Doppler ultrasound to measure aortic and mitral blood velocity and aortic pulse-wave velocity in 13-mo-old ApoE-KO and wild-type (WT) mice anesthetized with isoflurane. In other mice from the same colony, we measured systolic blood pressure, body weight, heart weight, cholesterol, and hematocrit. Heart rate and blood pressure were comparable (P = not significant) between ApoE-KO and WT mice, but significant decreases (P [is less than] 0.001) were found in body weight (-22%) and hematocrit (-11%), and significant increases were found in heart weight (+23%), aortic velocity (+60%), mitral velocity (+81%) (all P [is less than] 0.001), and pulse-wave velocity (+ 13%, P [is less than] 0.05). We also found inflections in the aortic arch velocity signal consistent with enhanced peripheral wave reflection. Thus ApoE-KO mice have phenotypic alterations in indexes of peripheral vascular resistance and compliance ,and significantly elevated cardiac outflow velocities and heart weight-to-body weight ratios. atherosclerosis; cardiac output; hypertrophy; ultrasonics

Wang, Yi-Xin, Meredith Halks-Miller, Ron Vergona, Mark E. Sullivan, Richard Fitch, Cornell Mallari, Baby Martin-McNulty, Valdeci Da Cunha, Ana Freay, Gabor M. Rubanyi, and Katalin Kauser. Increased aortic stiffness assessed by pulse wave velocity in apolipoprotein E-deficient mice. Am. J. Physiol. Heart Circ. Physiol. 278: H428-H434, 2000.--Atherosclerosis develops and progresses spontaneously in apolipoprotein E-knockout (apoE-KO) mice. A direct consequence of atherosclerosis is an increase in vascular stiffness. Pulse wave velocity (PWV) has been used to assess the stiffness of large vessels and was found to be increased in patients with atherosclerosis. In the present study, aortic stiffness was assessed by PWV in 4- and 13-mo-old apoE-KO mice and age-matched controls (C57BL/6J). In 13-mo-old apoE-KO mice with extensive atherosclerotic lesions in the aorta (61 [+ or -] 4%), PWV increased significantly (3.8 [+ or -] 0.2 m/s) compared with controls (2.9 [+ or -] 0.2 m/s). Endothelial nitric oxide (EDNO)-mediated vasorelaxation in response to ACh was markedly diminished in the aortic rings isolated from 13-mo-old apoE-KO mice compared with age-matched controls. In contrast, in 4-mo-old apoE-KO mice with only moderate atherosclerotic lesions in the aorta (23 [+ or -] 5%), there were no significant changes in PWV and EDNO-mediated relaxation compared with controls. Blood pressure was not different among the four groups of mice. There were no significant differences in endothelium-independent vascular responses to sodium nitroprusside among different groups investigated. Histological evaluation revealed focal fragmentation of the elastic laminae in the aortic walls of 13-mo-old apoE-KO mice. These results demonstrate for the first time that aortic stiffness determined by PWV increases in 13-mo-old apoE-KO mice. Endothelial dysfunction and elastic destruction in vascular wall caused by atherosclerosis may have contributed compliance; elastin degradation; endothelium-dependent relaxation; nitric oxide

Nitric oxide (NO) plays an important role in vascular protection. It has been reported that endothelial NO synthase (eNOS) deficiency exacerbated carotid artery ligation (CAL)-induced vascular remodeling, which, however, did not elucidate the role of inflammation. Overexpression of eNOS inhibited vascular inflammation and remodeling in a CAL model. However, there is no study that tested the hypothesis that eNOS deficiency can enhance the inflammatory response that plays a critical role in exacerbation of CAL-induced vascular remodeling. Thus, the present study used both eNOS knockout (eNOS-KO) mice and pharmacological blockade of nitric oxide synthase (NOS) to examine the temporal relationship between the inflammatory process and vascular remodeling by CAL and how elimination of NO production affects this. The left common carotid artery was ligated in eNOS-KO, or wild type (WT) mice treated with or without an NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). In WT mice, CAL induced vascular inflammation, characterized by neutrophil and macrophage infiltration into the vessel wall at 1 week. Although the inflammation diminished at 4 weeks, the ligated carotid artery developed prominent vascular remodeling, manifested by smooth muscle cell rich neointimal formation, medial thickening, and adventitial proliferation with reduced luminal diameter. CAL also increased the expression of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1). VCAM-1 peaked at 1 week, and then slightly declined 4 weeks after CAL, while MCP-1 continued to increase. In eNOS-KO mice, the above changes were exacerbated. Treatment with L-NAME resulted in similar changes as in eNOS-KO mice. Thus, in complement to the previous finding that eNOS overexpression inhibited CAL-induced vascular remodeling, the present study further demonstrated that the absence of eNOS exacerbated vascular remodeling by promoting MCP-1 and VCAM-1 mediated vascular inflammation. These data provided further in vivo evidence supporting the hypothesis that vasculo-protective effects of eNOS are mediated, at least in part, by inhibition of vascular inflammation and smooth muscle cell migration and proliferation induced by vascular injury and blood flow cessation. [ABSTRACT FROM AUTHOR]

The peroxisome proliferator-activated receptors (PPARs) have been shown to be important in modulating vascular inflammation and atherosclerosis. Angiotensin II (Ang II) is known to promote vascular inflammation and accelerate atherosclerosis. We demonstrated that these vascular changes induced by Ang II are associated with up-regulation of pro-inflammatory genes, as well as down-regulation of PPAR-α expression. We hypothesized that a PPAR-α agonist would have vasculoprotective effects in a mouse model of Ang II-induced atherosclerosis by: 1) attenuation of pro-inflammatory mediators, 2) attenuation of arterial low-density lipoprotein (LDL) accumulation, and 3) attenuation of endothelial layer permeability. To examine the effects of a PPAR-α agonist on vascular inflammation, we administered a diet containing fenofibrate (40 mg/kg/day) for 5 weeks to male apolipoprotein E-deficient (apoE-KO) mice that were infused with Ang II (1.44 mg/kg/day). Fenofibrate reversed the pro-inflammatory genes induced by Ang II, and upregulated PPAR-α mRNA expression in the aorta. To determine whether fenofibrate could reverse the functional consequences of Ang II, arterial LDL accumulation and endothelial layer permeability from isolated mouse carotid arteries were assessed by quantitative fluorescence microscopy. Fenofibrate significantly attenuated both the rate of arterial LDL accumulation and endothelial layer permeability induced by acute administration of Ang II. Our studies demonstrate that PPAR-α activation has functional effects to reduce LDL accumulation and endothelial layer permeability in the arterial wall. The pleiotropic effects of PPAR-&alpha agonists on vascular wall inflammation certainly participate in the inhibition of atherosclerosis development. [ABSTRACT FROM AUTHOR]

Dietary interventions can dramatically affect physiological health and organismal lifespan. The degree to which organismal health is improved depends upon genotype and the severity of dietary intervention, but neither the effects of these factors, nor their interaction, have been quantified in an outbred population. Moreover, it is not well understood what physiological changes occur shortly after dietary change and how these may affect the health of an adult population. In this article, we investigated the effect of 6-month exposure of either caloric restriction (CR) or intermittent fasting (IF) on a broad range of physiological traits in 960 1-year old Diversity Outbred mice. We found CR and IF affected distinct aspects of physiology and neither the magnitude nor the direction (beneficial or detrimental) of effects were concordant with the severity of the intervention. In addition to the effects of diet, genetic variation significantly affected 31 of 36 traits (her-itabilities ranged from 0.04 to 0.65). We observed significant covariation between many traits that was due to both diet and genetics and quantified these effects with phenotypic and genetic correlations. We genetically mapped 16 diet-independent and 2 diet-dependent significant quantitative trait loci, both of which were associated with cardiac physiology. Collectively, these results demonstrate the degree to which diet and genetics interact to shape the physiological health of adult mice following 6 months of dietary intervention. [ABSTRACT FROM AUTHOR]

In this study, we investigated if elevation of endogenous plasminogen activator inhibitor type 1 (PAI-1) by lipopolysaccharide (LPS) can retard thrombolysis in both a rat model of lung vasculature fibrin deposition and a platelet-rich thrombus model induced by endothelial injury. By 3 h following an intravenous bolus injection of 0.5 mg/kg LPS, the plasma PAI-1 level had increased to ∼8 ng/ml. 125I-labeled fibrinogen was injected intravenously followed by an injection of batroxobin. Batroxobin converts fibrinogen into insoluble fibrin, which was then deposited in the lungs within 5 min, followed by spontaneous fibrinolysis that completely cleared fibrin deposition in the lungs by 30 min. In rats pre-treated with LPS, spontaneous fibrinolysis was significantly retarded. In the endothelial injury model, topical application of FeCl2 on the carotid artery induced an occlusive platelet-rich thrombus, which was not sensitive to endogenous thrombolysis. Exogenous tissue-type plasminogen activator (tPA) was required to recanalize the occlusive thrombus in a dose-dependent manner. Pre-treatment with LPS did not alter the dose–response curve of exogenous tPA-induced thrombolysis. These data indicate that batroxobin-induced lung vasculature fibrin deposition in rats, unlike the FeCl2 model, is sensitive to the impact of endogenous PAI-1 on fibrinolysis. [Copyright &y& Elsevier]

Objective: Angiotensin II (Ang II) promotes vascular inflammation, accelerates atherosclerosis, and induces abdominal aortic aneurysm (AAA). These changes were associated with activation of nuclear factor (NF)-kappaB-mediated induction of proinflammatory genes. The incidence of AAA in this model was higher in male than in female mice, and the vascular effects of estrogen may be associated with anti-inflammatory actions. The present study was undertaken to test the hypothesis that estrogen can attenuate Ang II-induced AAA in apolipoprotein E-deficient mice via its anti-inflammatory mechanism., Methods and Results: Infusion of Ang II (1.44 mg/kg per d for 1 month) induced AAA in 90% of the animals (n=20) with an expansion of the suprarenal aorta (diameter 1.9+/-0.14 mm versus <1 mm in normal mice). In mice treated with 17beta-estradiol (E2, 0.25-mg subcutaneous pellets), Ang II induced AAA only in 42% of the animals (n=19) with a significant reduction of average diameters of the suprarenal aorta (1.5+/-0.14 mm). E2 also decreased the expressions of intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, E-selectin, monocyte chemotactic protein-1, and macrophage-colony stimulating factor in the aorta., Conclusions: These data suggest that attenuation of AAA by E2 is associated with inhibition of proinflammatory gene expression.

Angiotensin II (ANG II) promotes vascular inflammation through nuclear factor-kappaB (NF-kappaB)-mediated induction of pro-inflammatory genes. The role of peroxisome proliferator-activated receptors (PPARs) in modulating vascular inflammation and atherosclerosis in vivo is unclear. The aim of the present study was to examine the effects of ANG II on PPARs and NF-kappaB-dependent pro-inflammatory genes in the vascular wall in an in vivo model of atherosclerosis and aneurysm formation. Six-month-old male apolipoprotein E-deficient (apoE-KO) mice were treated with ANG II (1.44 mg/kg per day for 30 days). ANG II enhanced vascular inflammation, accelerated atherosclerosis, and induced formation of abdominal aortic aneurysms. These effects of ANG II in the aorta were associated with downregulation of both PPAR-alpha and PPAR-gamma mRNA and protein and an increase in transcription of monocyte chemotactic protein-1 (MCP-1), macrophage-colony stimulating factor (M-CSF), endothelial-selectin (E-selectin), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) throughout the entire aorta. ANG II also activated NF-kappaB with increases in both p52 and p65 NF-kappaB subunits. In summary, these in vivo results indicate that ANG II, through activation of NF-kappaB-mediated pro-inflammatory genes, promotes vascular inflammation, leading to acceleration of atherosclerosis and induction of aneurysm in apoE-KO mice. Downregulation of PPAR-alpha and -gamma by ANG II may diminish the anti-inflammatory potential of PPARs, thus contributing to enhanced vascular inflammation.