Abstract 310: Deoxycorticosterone Acetate (doca)-salt Exacerbates Hypertension and Vascular Dysfunction in Mice Expressing Dominant Negative Peroxisome Proliferator-activated Receptor-gamma (pparg) in Smooth Muscle

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Pimonrat Ketsawatsomkron ◽  
Deborah R Davis ◽  
Aline M Hilzendeger ◽  
Justin L Grobe ◽  
Curt D Sigmund
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Transgenic Mice ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Critical Role ◽  
Surrogate Marker ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that smooth muscle cell (SMC) PPARG protects against hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice, while the transgenic mice were tachycardic. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p<0.05 vs NT). Heart rate was similarly decreased in both groups after DOCA-salt. Vasoconstriction to KCl, phenylephrine and endothelin-1 did not differ in MA from DOCA-salt treated NT and S-P467L, while the response to vasopressin was significantly reduced in S-P467L after DOCA-salt (% constriction at 10-8 M, S-P467L: 31.6±5.6, NT: 46.7±3.8, p<0.05 vs NT). Urinary copeptin, a surrogate marker for arginine vasopressin was similar in both groups regardless of treatment. Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p<0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p<0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p<0.05 vs NT) in S-P467L MA after DOCA-salt. Expression of tissue inhibitor of metalloproteinases (TIMP)-4 and regulator of G-protein signaling (RGS)-5 transcript were 2- and 3.5-fold increased, respectively, in MA of NT with DOCA-salt compared to NT baseline. However, this induction was markedly blunted in S-P467L MA. We conclude that interference with PPARG function in SMC leads to altered gene expression crucial for normal vascular homeostasis, thereby sensitizing the mice to the effects of DOCA-salt induced HT and vascular dysfunction.

Abstract P264: Endothelial-specific Interference With PPARγ Activity in Offspring Born From AVP-induced Preeclamptic Pregnancies Has Cardio-renal and Metabolic Consequences

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Anand R Nair ◽  
Masashi Mukohda ◽  
Larry N Agbor ◽  
Ko-Ting Lu ◽  
Jing Wu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Female Offspring ◽  
Reduce Blood Pressure ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Hypertensive Disorder ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Impact

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor known to regulate metabolic and vascular function. Mutations in PPARγ result in hypertension, and synthetic agonists of PPARγ reduce blood pressure. Previously we found that mice expressing dominant-negative (DN) PPARγ driven by an endothelium-specific promoter (E-DN) exhibit vascular dysfunction. Preeclampsia (PE) is a hypertensive disorder of pregnancy which carries cardiovascular and metabolic risk to offspring. PE is associated with vascular dysfunction, and we therefore hypothesized a role for endothelial PPARγ in the pathogenesis of PE and its sequelae. C57BL/6J dams were bred with E-DN sires, and symptoms of PE were induced by the infusion of vasopressin (AVP, 24 ng/hr sc) throughout gestation. We assessed phenotypes of PE first in pregnant dams, and then in offspring as adults. Compared to saline infusion (SAL), AVP elevated maternal blood pressure (SBP: 116±3 vs 107±3, p<0.05) at gestational day (GD) 14-15 and urine protein (70±6 vs 27±4 mg/mL, p<0.05) at GD17. Offspring from these pregnancies were phenotyped in adulthood to assess cardiovascular and metabolic function. Data were stratified to sex, genotype, and maternal exposure to AVP vs SAL. Systolic blood pressure in adult male and female offspring born to AVP-infused pregnancies was similar to mice born to SAL pregnancies. At 20 weeks of age, vasorelaxation responses to acetylcholine were not different in offspring exposed to PE compared to mice born from SAL pregnancies. However, urinary protein levels were significantly elevated in both male (58±13 vs 32±5 mg/ml, p<0.05) and female (38±3 vs 25±2 mg/ml, p<0.05) adult E-DN born to PE pregnancies compared to E-DN controls born from SAL pregnancies. Male E-DN offspring exposed to PE showed significantly increased gain in body weight over time compared to male NT exposed to PE (ΔBW: 20±8 vs 14±2 g). These data highlight the impact of in utero exposure to elevated AVP upon cardiovascular function in the mother, and the adverse renal and metabolic consequences of PE upon offspring. Moreover, our data suggests that interference with endothelial PPARγ in pups born from PE pregnancies increases the risk for renal and metabolic dysfunction.

Abstract 053: RhoBTB1 is a Novel Gene Protecting Against Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Masashi Mukohda ◽  
Stella-Rita C Ibeawuchi ◽  
Chunyan Hu ◽  
Ko-Ting Lu ◽  
Debbie R Davis ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Thoracic Aorta ◽  
Basilar Artery ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Dominant Negative ◽  
Tamoxifen Treatment ◽  
Peroxisome Proliferator ◽  
Ang Ii ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand activated transcription factor regulating metabolic and vascular function. We previously reported that mice (S-DN) expressing dominant-negative PPARγ in smooth muscle cells (SMC) are hypertensive, exhibit impaired vascular relaxation and enhanced contraction, and display reduced expression of a novel PPARγ target gene, RhoBTB1. We hypothesized that RhoBTB1 may play a protective role in vascular function that is disrupted in S-DN mice and in other models of hypertension. We generated double transgenic mice (termed R+) with tamoxifen-inducible, Cre-dependent expression of RhoBTB1 in SMC. R+ mice were crossed with S-DN to produce mice (S-DN/R+) in which tamoxifen-treatment (75 mg/kg, ip, 5 days) restored RhoBTB1 expression in aorta to normal. Thoracic aorta and basilar artery from S-DN showed impaired acetylcholine (ACh)-induced endothelial-dependent relaxation, which was reversed by replacement of RhoBTB1 in SMC (thoracic aorta, 43.3±4.4 vs 74.2±1.1%, p<0.01, basilar artery, 19.9±6.7 vs 48.1±12.3%, p<0.05, n=6). Aorta from S-DN mice also displayed severely decreased sodium nitroprusside (SNP)-induced endothelial-independent relaxation with a right-shifted dose-response, which was also reversed in tamoxifen-treated S-DN/R+ mice (p<0.01, n=6). Importantly, replacement of RhoBTB1 also reversed the hypertensive phenotype observed in S-DN mice (Radiotelemetry SBP, 135.9±3.9 vs 123.7±3.0 mmHg, p<0.05, n=4). To examine if overexpression of RhoBTB1 in SMC has a protective effect on other hypertensive models, Ang-II (490 ng/min/kg) was infused in tamoxifen treated R+ mice for 2 wks. RhoBTB1 expression prevented Ang-II-induced impairment of ACh relaxation in basilar artery (17.0±8.6 in control mice vs 40.7±5.3 % in R+ mice, p<0.05, n=4) and decreased SBP (166.0±7.2 in control mice vs 133.3±5.1 mmHg in R+ mice, p<0.05, n=4). We conclude that a) loss of RhoBTB1 function explains the vascular dysfunction and hypertension observed in response to interference with PPARγ in smooth muscle, and b) RhoBTB1 in SMC has an anti-hypertensive effect and facilitates vasodilatation.

Abstract 10: Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice in vivo

Stroke ◽  
2016 ◽  
Vol 47 (suppl_1) ◽  
Author(s):  
Robert M Starke ◽  
He Gu ◽  
Katina Wilson ◽  
Yi Chu ◽  
Nohra Chalouhi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Inflammation ◽  
Critical Role ◽  
Cerebral Aneurysms ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Nuclear Factor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Aneurysm Formation ◽  
Pparγ Agonist

Background and Purpose: Vascular inflammation plays a critical role in the pathogenesis of cerebral aneurysms. Peroxisome proliferator-activated receptor γ (PPARγ) protects against vascular inflammation and atherosclerosis, whereas dominant-negative mutations in PPARγ promote atherosclerosis and vascular dysfunction. In this study, the role of PPARγ in aneurysm formation and rupture was tested. Methods: Aneurysms were induced with a combination of systemic infusion of angiotensin-II and local injection of elastase in (1) mice that received the PPARγ antagonist GW9662 or the PPARγ agonist pioglitazone, (2) mice carrying dominant-negative PPARγ mutations in endothelial or smooth muscle cells, and (3) mice that received the Cullin inhibitor MLN4924. Incidence of aneurysm formation, rupture, and mortality was quantified. Cerebral arteries were analyzed for expression of Cullin3, Kelch-like ECH-associated protein 1, nuclear factor (erythroid-derived 2)-like 2, NAD(P)H dehydrogenase (quinone)1 (NQO1), and inflammatory marker mRNAs. Results: Neither pioglitazone nor GW9662 altered the incidence of aneurysm formation. GW9662 significantly increased the incidence of aneurysm rupture, whereas pioglitazone tended to decrease the incidence of rupture. Dominant-negative endothelial-specific PPARγ did not alter the incidence of aneurysm formation or rupture. In contrast, dominant-negative smooth muscle-specific PPARγ resulted in an increase in aneurysm formation (P<0.05) and rupture (P=0.05). Dominant-negative smooth muscle-specific PPARγ, but not dominant-negative endothelial-specific PPARγ, resulted in significant decreases in expression of genes encoding Cullin3, Kelch-like ECH-associated protein 1, and nuclear factor (erythroid-derived 2)-like 2, along with significant increases in tumor necrosis factor-α, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligand 1, CD68, matrix metalloproteinase-3, -9, and -13. MLN4924 did not alter incidence of aneurysm formation, but increased the incidence of rupture (P<0.05). Conclusions: Endogenous PPARγ, specifically smooth muscle PPARγ, plays an important role in protecting from formation and rupture of experimental cerebral aneurysms in mice.

scholarly journals Failure to vasodilate in response to salt loading blunts renal blood flow and causes salt-sensitive hypertension

2020 ◽  
Author(s):  
Jing Wu ◽  
Larry N Agbor ◽  
Shi Fang ◽  
Masashi Mukohda ◽  
Anand R Nair ◽  
...  
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Renal Blood Flow ◽  
Vascular Dysfunction ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Salt Loading ◽  
Dominant Negative Mutation ◽  
Induced Hypertension

Abstract Aims Salt-sensitive (SS) hypertension is accompanied by impaired vasodilation in the systemic and renal circulation. However, the causal relationship between vascular dysfunction and salt-induced hypertension remains controversial. We sought to determine whether primary vascular dysfunction, characterized by a failure to vasodilate during salt loading, plays a causal role in the pathogenesis of SS hypertension. Methods and results Mice selectively expressing a peroxisome proliferator-activated receptor γ dominant-negative mutation in vascular smooth muscle (S-P467L) exhibited progressive SS hypertension during a 4 week high salt diet (HSD). This was associated with severely impaired vasodilation in systemic and renal vessels. Salt-induced impairment of vasodilation occurred as early as 3 days after HSD, which preceded the onset of SS hypertension. Notably, the overt salt-induced hypertension in S-P467L mice was not driven by higher cardiac output, implying elevations in peripheral vascular resistance. In keeping with this, HSD-fed S-P467L mice exhibited decreased smooth muscle responsiveness to nitric oxide (NO) in systemic vessels. HSD-fed S-P467L mice also exhibited elevated albuminuria and a blunted increase in urinary NO metabolites which was associated with blunted renal blood flow and increased sodium retention mediated by a lack of HSD-induced suppression of NKCC2. Blocking NKCC2 function prevented the salt-induced increase in blood pressure in S-P467L mice. Conclusion We conclude that failure to vasodilate in response to salt loading causes SS hypertension by restricting renal perfusion and reducing renal NO through a mechanism involving NKCC2 in a mouse model of vascular peroxisome proliferator-activated receptor γ impairment.

Abstract 331: Mutation in the PPARG Ligand Binding Domain Impairs PPARG-Mediated Turnover of the p65 Subunit of NF-kB

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Masashi Mukoda ◽  
Madeliene Stump ◽  
Pimonrat Ketsawatsomkron ◽  
Frederick W Quelle ◽  
Curt D Sigmund
Keyword(s):  
Vascular Function ◽  
Nuclear Factor Kappa B ◽  
Vascular Dysfunction ◽  
Direct Interaction ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Transfected Cells ◽  
Over Expression ◽  
Pparγ Agonist

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand activated transcription factor regulating metabolic and vascular function. PPARγ exerts anti-inflammatory actions, and recent data suggest this may be mediated by promoting the degradation of the p65 subunit of nuclear factor kappa B (NFκB). Transgenic mice expressing dominant negative PPARγ specifically in vascular smooth muscle or endothelium exhibited exacerbated atherosclerosis but the mechanism remains unknown. We hypothesized that PPARγ mutants promote inflammation because PPARγ-mediated p65 degradation is impaired. We tested this by co-transfection of HEK293T cells with vectors encoding p65, wildtype (WT) PPARγ, or various PPARγ mutants. The level of p65 protein expression was decreased by co-expression with WT-PPARγ (0.53±0.09 vs control, n=8). Whereas, the P467L PPARγ exhibited impaired degradation of p65 (1.0±0.06, n=10), the V290M (0.36±0.1), S273A (0.37±0.06), or K268R/K293R (0.41±0.03) mutations in PPARγ preserved p65 degradation. WT PPARγ was co-precipitated with p65 in co-transfected cells suggesting the mechanism of PPARγ-mediated p65 degradation involves a direct interaction between them. Consistent with this, the interaction between p65 and P467L PPARγ was severely impaired. To assess functional interactions between PPARγ and NFκB, we employed a model of interleukin-1β (IL-1β) mediated dysfunction in aortic rings. IL-1β dose-dependently induced NFκB activity as measured by increased phospho-p65 and decreased IκBα in aorta cultured for 2 hours with IL-1β. IL-1β dose-dependently reduced acetylcholine (Ach)-induced endothelial-dependent relaxation of aortic rings (80±12 vs 39±16, 20 pg/mL vs 11±3, 100 pg/mL, %). IL-1β-mediated loss of Ach vasodilation was reduced by the PPARγ agonist rosiglitazone (1 μM, 25 hr, n=3, p<0.05), or by transgenic over-expression of WT-PPARγ specifically in endothelium (n=6, p<0.05). We conclude that 1) p65 turnover may be regulated by PPARγ and that its mutation can result in impaired p65 degradation, 2) PPARγ activity can protect against vascular dysfunction associated with NFκB activation, and 3) loss of PPARγ-mediated p65 degradation may contribute to inflammation in hypertension and atherosclerosis.

Abstract MP23: Vascular Smooth Muscle Rho-related Btb Domain Containing Protein 1 In Hypertension And Arterial Stiffness

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Shi Fang ◽  
Jing Wu ◽  
Sebastiao Donato Silva ◽  
Ko-ting Lu ◽  
Curt D Sigmund
Keyword(s):  
Smooth Muscle ◽  
Arterial Stiffness ◽  
Vascular Smooth Muscle ◽  
Vascular Dysfunction ◽  
Dominant Negative ◽  
Hek293 Cells ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Btb Domain

Rho-related BTB domain containing protein 1 (RhoBTB1) is a transcriptional target of peroxisome proliferator activated receptor γ (PPARγ), but its physiological and molecular function in blood pressure (BP) control remains unclear. We showed that aortic RhoBTB1 expression was decreased in mice expressing vascular smooth muscle (VSM) specific dominant negative PPARγ mutation (S-P467L). Genetic complementation of VSM RhoBTB1 reversed the hypertension, vascular dysfunction, and arterial stiffness in S-P467L mice; and suppressed the elevated enzymatic activity of phosphodiesterase 5 (PDE5) in S-P467L mice. In HEK293 cells, RhoBTB1 increases PDE5 ubiquitination in a Cullin-3-dependent manner. We concluded that VSMC RhoBTB1 mediates the anti-hypertensive effect of PPARγ. RhoBTB1 expression was decreased in aorta from mice treated with angiotensin II (AngII, 490ng/kg/min, 2-weeks). We hypothesized that restoration of VSM RhoBTB1 would reverse established AngII-mediated hypertension, vascular dysfunction, and arterial stiffness. Transgenic mice expressing inducible VSM-specific RhoBTB1 (S-RhoBTB1) were treated with AngII (490ng/kg/min, 6-weeks) and the transgene was activated by Tamoxifen (Tx) during week 3. ISM-Cre mice expressing VSM Cre-recombinase were similarly treated as controls. AngII equally increased BP, as measured by radiotelemetry in both ISM-Cre and S-RhoBTB1 mice. The vasodilatory and vasoconstrictor responses in the carotid artery were not different in AngII-treated S-RhoBTB1 and ISM-Cre mice. RhoBTB1 did not affect pulse wave velocity (PWV), a measure of arterial stiffness, in mice without AngII (ISM-Cre vs S-RhoBTB1: 2.64±0.08 vs 2.48±0.06 mm/ms, p>0.05, n=6); and AngII increased PWV similarly in both strains before Tx (ISM-Cre vs S-RhoBTB1: 3.54±0.22 vs 3.52±0.18 mm/ms, p>0.05, n=7-9). PWV of S-RhoBTB1 mice started to decrease after the first week whereas it continued to rise in ISM-Cre mice. By the second week of Tx, VSMC RhoBTB1 expression significantly attenuated AngII induced arterial stiffness (ISM-Cre vs S-RhoBTB1: 4.21±0.37 vs 3.17±0.16 mm/ms, p=0.02, n=7-9). These data suggest a mechanism where RhoBTB1 improves vascular compliance independently from BP and is protective against arterial stiffness.

scholarly journals Regulator of G protein signaling 5 is a determinant of gestational hypertension and preeclampsia

2015 ◽  
Vol 7 (290) ◽  
pp. 290ra88-290ra88 ◽  
Author(s):  
Vasyl Holobotovskyy ◽  
Yee Seng Chong ◽  
Jennifer Burchell ◽  
Bo He ◽  
Michael Phillips ◽  
...  
Keyword(s):  
Blood Pressure ◽  
G Protein ◽  
Vascular Function ◽  
Gestational Hypertension ◽  
Peroxisome Proliferator ◽  
Protein Signaling ◽  
Current Standard ◽  
Guanine Nucleotide Binding Protein ◽  
Peroxisome Proliferator Activated Receptor

Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide–binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator–activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia.

scholarly journals Salt-Sensitivity of Blood Pressure and Insulin Resistance

2021 ◽  
Vol 12 ◽  
Author(s):  
Lale A. Ertuglu ◽  
Fernando Elijovich ◽  
Cheryl L. Laffer ◽  
Annet Kirabo
Keyword(s):  
Insulin Resistance ◽  
Blood Pressure ◽  
Insulin Sensitivity ◽  
Immune Activation ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Salt Sensitivity ◽  
Common Denominator ◽  
Peroxisome Proliferator ◽  
Cardiovascular Morbidity And Mortality

Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular morbidity and mortality that is seen in both hypertensive and normotensive populations. Insulin resistance (IR) strongly correlates with SSBP and affects nearly 50% of salt sensitive people. While the precise mechanism by which IR and SSBP relate remains elusive, several common pathways are involved in the genesis of both processes, including vascular dysfunction and immune activation. Vascular dysfunction associated with insulin resistance is characterized by loss of nitric oxide (NO)-mediated vasodilation and heightened endothelin-1 induced vasoconstriction, as well as capillary rarefaction. It manifests with increased blood pressure (BP) in salt sensitive murine models. Another common denominator in the pathogenesis of insulin resistance, hypertension, and salt sensitivity (SS) is immune activation involving pro-inflammatory cytokines like tumor necrosis factor (TNF)-α, IL-1β, and IL-6. In the last decade, a new understanding of interstitial sodium storage in tissues such as skin and muscle has revolutionized traditional concepts of body sodium handling and pathogenesis of SS. We have shown that interstitial Na+ can trigger a T cell mediated inflammatory response through formation of isolevuglandin protein adducts in antigen presenting cells (APCs), and that this response is implicated in salt sensitive hypertension. The peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that modulates both insulin sensitivity and BP. PPARγ agonists increase insulin sensitivity and ameliorate salt sensitivity, whereas deficiency of PPARγ results in severe insulin resistance and hypertension. These findings suggest that PPARγ plays a role in the common pathogenesis of insulin sensitivity and salt sensitivity, perhaps via effects on the immune system and vascular function. The goal of this review is to discuss those mechanisms that may play a role in both SSBP and in insulin resistance.

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