Mineralocorticoid Receptor-Mediated Vascular Insulin Resistance: An Early Contributor to Diabetes-Related Vascular Disease?

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by  Bender, Shawn B.

PERSPECTIVESINDIABETES
Mineralocorticoid Receptor–Mediated Vascular
Insulin Resistance
An Early Contributor to Diabetes-Related Vascular
Disease?
Shawn B. Bender,1,2 Adam P. McGraw,3 Iris Z. Jaffe,3 and James R. Sowers1,2,4
Two-thirds of adults in the U.S. are overweight or obese, and
another 26 million have type 2 diabetes (T2D). Patients with
diabetes and/or the metabolic syndrome have a significantly
increased risk of heart attack and stroke compared with people
ALDOSTERONEANDCARDIOVASCULARRISK
with normal insulin sensitivity. Decreased insulin sensitivity in
cardiovascular tissues as well as in traditional targets of insulin Epidemiological studies demonstrate a clear correlation
metabolic signaling, such as skeletal muscle, is an underlying between elevated aldosterone levels and increased rates
abnormality in obesity, hypertension, and T2D. In the vascula- of cardiovascular disease (CVD) in patients with and
ture, insulin signaling plays a critical role in normal vascular withoutprimaryhyperaldosteronism(1,2).Furthermore,it
function via endothelial cell nitric oxide production and modu- iswell-establishedthatinhibitorsoftherenin–angiotensin–
lationofCa2+handlingandsensitivityinvascularsmoothmuscle
aldosterone system (RAAS) reduce cardiovascular ische-
cells. Available evidence suggests that impaired vascular insulin
mic events (i.e., heart attack and stroke) and mortality
sensitivitymaybeanearly,perhapsprincipal,defectofvascular
functionandcontributortothepathogenesisofvasculardisease (3–6). This is true of antagonists to angiotensin II (Ang II)
inpersonswithobesity,hypertension,andT2D.Intheoverweight (converting enzyme [ACE] and receptor blockade) in mul-
and obese individual, as well as in persons with hypertension, tiple patient populations including patients with diabetes
systemic and vascular insulin resistance often occur in concert (4).TheEplerenonePost-AcuteMyocardialInfarctionHeart
withelevationsinplasmaaldosterone.Indeed,basicandclinical Failure Efficacy and Survival Study (EPHESUS) and Ran-
studieshavedemonstratedthatelevatedplasmaaldosteronelev- domizedAldactoneEvaluationStudy(RALES)trials,among
els predict the development of insulin resistance and that others, extended these beneficial findings to mineralocorti-
aldosterone directly interferes with insulin signaling in vascular
coid receptor (MR) antagonists with pronounced reduc-
tissues. Furthermore, elevated plasma aldosterone levels are as-
tions of cardiovascular mortality reported in patients with
sociatedwithincreasedheartattackandstrokerisk.Conversely,
renin–angiotensin–aldosterone system and mineralocorticoid re- acute myocardial infarction/heart failure and severe heart
ceptor(MR)antagonismreducescardiovascularriskinthesepa- failure, respectively (5,6). These trials were the first to
tientpopulations.Recentandaccumulatingevidenceinthisarea examine the effect of MR antagonism, in addition to
has implicated excessive Ser phosphorylation and proteosomal standard therapy (including ACE inhibitors), on cardio-
degradation of the docking protein, insulin receptor substrate, vascular outcomes in these patient populations. Post hoc
and enhanced signaling through hybrid insulin/IGF-1 receptor
analysis of the EPHESUS trial suggested a greater abso-
asimportantmechanismsunderlyingaldosterone-mediatedinter-
lute risk reduction in diabetic patients compared with
ruption of downstream vascular insulin signaling. Prevention or
nondiabetics treated with eplerenone (7). Additionally,
restoration of these changes via blockade of aldosterone action
in the vascular wall with MR antagonists (i.e., spironolactone, failure of the clinical trial for the HDL-raising cholesteryl
eplerenone) may therefore account for the clinical benefit of ester transfer protein inhibitor torcetrapid has recently
these compounds in obeseand diabeticpatients with cardiovas- been associated with off-target elevations of plasma al-
culardisease.Thisreviewwillhighlightrecentevidencesupport- dosterone that correlated with increased atherosclerosis,
ing the hypothesis that aldosterone and MR signaling represent ischemia, and death (8,9). Notable recent work has
an ideal candidate pathway linking early promoters of diabetes,
revealedthatelevationsofplasmaaldosterone,withinthe
especially overnutrition and obesity, to vascular insulin resis-
normal range, are associated with increased ischemic
tance,dysfunction, anddisease.Diabetes 62:313–319, 2013
events and CVD death in patients with coronary artery
diseasebutnormalcardiacfunction(2).Inthecontextof
diabetes, subset analysis revealed that diabetic patients
with small elevations in plasma aldosterone within the
Fromthe1DepartmentofInternalMedicine,UniversityofMissouriSchoolof normal range exhibited a 10% increase in CVD mortality
Medicine, Columbia, Missouri; the 2Diabetes and Cardiovascular Center, relative to diabetic patients with low-normal aldosterone
Harry S. Truman VA Medical Center, Columbia, Missouri; the 3Molecular
levels (2). Furthermore, MR blockade with eplerenone in
Cardiology Research Institute, Tufts Medical Center, Boston, Massachu-
setts;andthe4DepartmentofMedicalPharmacologyandPhysiology,Uni- diabetic patients already receiving ACE inhibitor therapy
versityofMissouriSchoolofMedicine,Columbia,Missouri. improved coronary flow reserve (10). Thus, clinical evi-
Correspondingauthor:ShawnB.Bender,[email protected]. dence supports substantial cardiovascular benefit of MR
Received6July2012andaccepted7August2012.
DOI:10.2337/db12-0905 antagonism, particularly in patients with diabetes.
(cid:1)2013bytheAmericanDiabetesAssociation.Readersmayusethisarticleas An important finding in many of these clinical studies
longastheworkisproperlycited,theuseiseducationalandnotforprofit, and others is that the benefit of MR antagonism to reduce
and the work is not altered. See http://creativecommons.org/licenses/by
-nc-nd/3.0/fordetails. CVDoutcomesoccurseitherindependentofbloodpressure
diabetes.diabetesjournals.org DIABETES,VOL.62,FEBRUARY2013 313
MR-MEDIATEDVASCULARINSULINRESISTANCE
changes or is disproportionately greater than would be Vascularinsulinresistance.Aprimaryfeatureofinsulin
expected by the reported changes in blood pressure resistance whether in skeletal muscle or vascular cells is
(1,3,6,7,10). Clinically, MR antagonists are widely pre- the selective impairment of insulin-stimulated IRS/PI3K
scribed antihypertensives owing to their diuretic action at signaling with little change of insulin signaling via MAPK
the distal tubule and collecting duct. Thus, the disparate andothergrowthpathways(15).Consequently,theactions
relationshipbetweenthebloodpressure-andCVD-lowering of insulin to modulate the contractile state of VSMCs di-
effectsofMRantagonistssuggeststhattheseagentsconfer rectly (i.e., via Ca2+ handling) and via EC NO production
protection through renal- and blood pressure–independent are attenuated. Furthermore, downstream antioxidant,
mechanismsincludingdirecteffectsincardiovasculartissue. anti-inflammatory, and antiatherogenic effects of insulin
Inthevasculature,functionalaldosterone-sensitiveMRshave signaling via IRS/PI3K are also reduced. Thus, in the face
beendescribedinbothendothelialcells(ECs)andvascular of insulin resistance-associated hyperinsulinemia, insulin-
smoothmusclecells(VSMCs)(11,12).Importantly,studies mediated MAPK signaling to oxidative, proliferative, in-
have recently revealed a role for vascular-specific MR in flammatory, and mitogenic pathways, including ET-1, is
vascularcellgeneexpression,injury,andpathology(3,13,14). typically augmented. This scenario of reduced NO pro-
The remainder of this review will focus on recent studies duction and enhanced production of vasoconstrictor fac-
examining the impact of aldosterone and MR signaling on tors such as ET-1 is a characteristic feature of vascular
vascular insulin metabolic signaling and the potential role dysfunction in insulin-resistant states (17,18). In vivo, this
ofMR-mediatedimpairmentsinvascularinsulinsensitivity results in blunted insulin-induced vasodilation, capillary
as an early defect in vascular function in insulin-resistant recruitment, and glucose disposal across skeletal muscle
states. vascular beds (15,19).
VASCULARINSULINSIGNALINGANDRESISTANCE ISVASCULARINSULINRESISTANCEANEARLY
Insulin metabolic signaling is an important contributor to CONTRIBUTORTOVASCULARDISEASE?
normalvascularfunctionandhomeostasis.Muchefforthas Ithasbeenacceptedformanyyearsthatsignsofsystemic
been focused on delineating the various pathways for and insulin resistance (e.g., hyperinsulinemia) are harbingers
rolesofinsulinsignalinginvascularcells,andthismaterial ofmorewidespreadandseverediseaseprocesses.Thus,it
has been reviewed elsewhere (15). Beyond its systemic seems reasonable to inquire whether resistance to the
metabolicactions,insulinsignalsinvascularcellsviaparallel vascular effects of insulin precedes other defects of vas-
pathways downstream of the insulin receptor (IR) that ac- cular function commonly found in CVD states. There is
countforthewell-describedvasomotoreffectsofinsulin(15). a dearth of available information directly addressing this
Insulin effects in ECs. Briefly, in vascular ECs, insulin question,assuchstudiesrequire,ataminimum,theuseof
stimulates production of the vasodilator nitric oxide (NO) animals with very early stage disease in which vasomotor
via activation of IR substrate (IRS)-1/phosphatidylinositol responses to insulin and other vasomotor agents are ex-
3-kinase (PI3K) signaling (Fig. 1) (15). In contrast, insulin amined simultaneously. A cross-sectional examination of
alsostimulatesproductionofthevasoconstrictorendothelin-1 available data, however, offers some evidence of such a
(ET-1) via Ras/mitogen-activated protein kinase (MAPK)– scenario.
dependent signaling (15). Thus, vascular insulin signaling The most compelling evidence that vascular insulin re-
involves a balance between vasodilator/anti-inflammatory/ sistance occurs prior to widespread vascular dysfunction
antiatherogenic(IRS/PI3K/NO)signalingandvasoconstrictor/ comes from studies using the Zucker obese (ZO) rat
proinflammatory/proatherogenic growth (Ras/MAPK/ET-1) model. In cremaster muscle arterioles from 14–16-week-
signaling pathways. Although some controversy remains, old ZO rats, impaired insulin-induced vasodilation has
the majority of evidence in animal and human studies been demonstrated in the absence of impaired dilation to
demonstrates that, in healthy subjects, insulin induces acetylcholine (20). This is consistent with evidence from
endothelium- and NO-dependent vasodilation in vivo and coronary arterioles in the ZO model in which insulin-
in vitro. Further, the beneficial actions of insulin-induced inducedvasodilation isattenuated as early as 12 weeks of
NO production appropriately limit the contractile, prolifer- age, whereas acetylcholine-induced vasodilation is im-
ative, and inflammatory actions of insulin-stimulated growth paired much later at 28–36 weeks of age (21,22). These
factor production (reviewed in Ref. 15). studies are especially noteworthy as they demonstrate
Insulin effectsin VSMCs. In addition to the endothelial earlyvascularinsulinresistanceintheskeletalandcardiac
actions of insulin leading to vasodilation, insulin pro- muscle microcirculation, the primary site of tissue blood
motesvasodilationviadirectactioninVSMCstomodulate flow control. Early vascular insulin resistance has also
Ca2+ handling and sensitivity (16). Specifically, insulin beenreportedinrodentmodelsofhypertensionandaging.
reduces agonist-mediated vasoconstriction inendothelium- Specifically, aortic dilation to insulin, but not acetylcho-
denuded rat aorta and contraction of cultured VSMCs in line,isreducedinthespontaneouslyhypertensiveratprior
vitro(16).Subsequentworkrevealedthatinsulinactstolimit to the onset of hypertension (23) and in aged (24-month-
Ca2+ influx through receptor- and voltage-gated Ca2+ chan- old) rats (24). Data from these studies remain equivocal
nels and enhances Ca2+ efflux via Ca2+-ATPase (16). In ad- regarding the potential involvement of increased reactive
dition, insulin acts to reduce Ca2+ sensitivity of VSMC oxygen species (ROS) formation in reducing vascular in-
contractile machinery via activation of myosin phospha- sulin signaling, particularly in ECs. Thus, vascular insulin
tase and decreased myosin light chain phosphorylation resistance appears to be an early vascular defect in
(16). Similar to insulin signaling in ECs, evidence demon- multiple disease models and may serve as a unifying hy-
stratesthatinsulinactionsinVSMCsrequirePI3K/inducible pothesis for widespread vascular disease. Furthermore, a
NO synthase/cyclic guanosine monophosphate signaling contribution of EC insulin resistance to the development
(16). Thus, insulin signals through the IRS/PI3K pathway in of more global EC dysfunction (i.e., dysfunction involving
both ECs and VSMCs to induce vasodilation. otherpathwaysregulatingNOproduction)issuggestedby
314 DIABETES,VOL.62,FEBRUARY2013 diabetes.diabetesjournals.org
S.B.BENDERANDASSOCIATES
FIG.1.MR-dependenteffectsonendothelialandSMCfunctionandinsulinsignaling.Invascularcells,MRactivationleadstoattenuatedinsulin
signalingandultimatelyreducedinsulin-inducedvasodilation.Thisinvolvesactivationofredox-sensitiveand-insensitiveserinekinases(SerKs),
degradationofIRS-1,reducedIRS-1signalingviaPI3K,reducedproductionofNO,andincreasedsmoothmuscleCa2+levelsandsensitization.MR
activation also promotes a proatherogenic vascular phenotype via increased endothelial expression of ICAM-1 as well as increased insulin-
mediatedgrowthsignalinginSMCs.Up(↑)anddown(↓)arrowsindicateeffectsofaldosterone/MRand/orAngIIsignalingonspecificmolecules.
Akt-P, phosphorylated protein kinase B; Aldo, aldosterone; eNOS-P, phosphorylated endothelial NO synthase; MLC-P, phosphorylated myosin
lightchain;SerP,serinephosphorylation;TyrP,tyrosinephosphorylation.
the presence of endothelial dysfunction in mice with EC- production and is elevated in adipose tissue of obese
specific insulin resistance and in human carriers of the rodents (30). Secondly, dietary salt restriction, which
IRS-1 Arg972 polymorphism (25,26). Thus, a better under- increases aldosterone production, also induces vascular
standing of the precipitating factors and mechanisms un- insulin resistance, as reflected in reduced insulin-induced
derlying early defects in vascular insulin signaling is vasodilation in healthy subjects (28). Finally, mild ele-
acriticalareaofresearchandanexcitingtargetforfuture vations of plasma aldosterone within the normal range
therapeutics. increase cardiovascular mortality in patients with coro-
nary artery disease (2). This evidence supports the notion
thataldosteroneproductionisrelatedtoadiposityandthat
ALDOSTERONEANDVASCULARINSULINRESISTANCE even mild elevations in plasma aldosterone confer signifi-
Associations among aldosterone, obesity, and CVD. cant effects on vascular insulin sensitivity and cardiovas-
Based on recent and accumulating reports, we posit that cular outcomes. Although we believe MR signaling to be
aldosterone and MR signaling represents an ideal candi- a primary player in outcomes related to overnutrition and
date pathway linking early promoters of diabetes, espe- obesity, we recognize that other adipokines also likely
cially overnutrition and obesity, to vascular insulin contribute to vascular insulin resistance in vivo. Thus, al-
resistance, dysfunction, and disease (Fig. 2). This is sup- dosterone and MR signaling likely converge with other
ported by several parallel lines of evidence. First, strong systemic (i.e., adipokines) and local factors related to
associations of aldosterone, MR signaling, and systemic overnutrition. One example is activation of the nutrient-
insulin resistance have been reported and reviewed else- sensingmammaliantargetofrapamycinpathwaytoimpair
where (27,28). Importantly, plasma aldosterone is corre- insulin signaling in vascular tissues. With regard to the
lated with BMI and insulin resistance in normotensive pathogenesis of diabetes and CVD, however, we believe
subjects (29). A link between progressive elevations of available evidence supports a principal role for pro-
plasmaaldosteroneandBMIisfurthersuggestedbyrecent gressiveelevationsinaldosteroneproductionandvascular
evidence that the novel adipokine complement-C1q tumor MR activation, related to increases in adiposity, in the
necrosis factor–related protein 1 stimulates aldosterone development of systemic and vascular insulin resistance.
diabetes.diabetesjournals.org DIABETES,VOL.62,FEBRUARY2013 315
MR-MEDIATEDVASCULARINSULINRESISTANCE
glucose metabolism while augmenting insulin-stimulated
extracellular signal-regulated kinase 1/2 phosphorylation
and hypertrophic signaling in VSMCs (i.e., protein syn-
thesis) (32). This is consistent with previous work dem-
onstrating aldosterone-mediated enhancement of IGF-1
signaling in VSMCs (37). With regard to insulin signaling,
however, these results suggest that high levels of insulin,
asoccursininsulinresistance,maysignalthroughIGF-1R
or hybrid receptors that are upregulated by aldosterone.
Expression of the IR was not changed by aldosterone
treatment, suggesting that the increase in hybrid receptor
occurredviaincreasedIGF-1Randsubsequentassociation
with IR (32). Although the role of IGF-1R and hybrid re-
ceptor signaling remains unclear in VSMCs, particularly
with regard to vascular protective versus pathological
effects, this study has improved our understanding of the
potential mechanisms underlying the increased cardio-
vascularriskassociatedwithelevationsinaldosteroneand
MR signaling. However, important questions remain re-
garding the specific signaling cascades activated by aldo-
sterone leading to degradation of IRS-1 and upregulation
of IGF-1R and whether these are genomic or nongenomic
effects of MR activation.
FIG. 2. Schematic model representing the relationships and inter- AldosteroneandinsulinresistanceinECs.Aldosterone
actionsamongobesity,diabetes,vascularaldosterone/MR,andinsulin and MR signaling is also known to contribute to vascular
signalingthatcontributetoheartattackandstroke.eNOS,endothelial
EC function (3,11); however, no study has directly exam-
NOsynthase.
inedMR-dependenteffectsonECinsulinsignaling.Thisis
anintriguingareaoffutureresearchgivenmultiplereports
Aldosterone-induced insulin resistance in VSMCs. ofimprovedendothelialfunctioninvariousdiseasemodels
Although aldosterone has been linked to impaired in- following treatment with MR antagonists (38). Further-
sulin-induced vasodilation, few studies have examined more,availabledatademonstrateactivationofvariousSer
underlyingmechanism(s)invascularcells.Recentseminal kinases and reductions in EC IRS-1 protein insulin signal-
work in VSMCs, however, demonstrates pronounced ef- ing in models of insulin resistance (39). Although inter-
fects ofaldosteronetolimitinsulinsignalingandactionin actions between EC MR and insulin signaling have not
thevasculature(Fig.1)(31,32).Thesereportsdemonstrate been described, insight regarding putative mechanisms
effects of aldosterone at the level of both IRS-1 and via underlying MR-insulin cross talk may be garnered from
IGF-1receptor(IGF-1R)(31,32).RegardingeffectsonIRS-1, studies that have examined Ang II-dependent attenuation
aldosterone treatment of cultured VSMCs increases pro- of EC insulin signaling. This is particularly relevant given
teosomal degradation of IRS-1 and attenuates insulin- evidence of substantial cross-activation between vascular
induced Akt phosphorylation and glucose uptake (31). MR and angiotensin type I receptors (AT1Rs) by their re-
This effect was prevented by MR blockade, Src inhibition, spective ligands and that MR blockade attenuates Ang
and antioxidants, indicating a role for MR-dependent ac- II-induced vascular damage (12,14). Attenuation of insulin
tivation of Src and ROS generation. These results are in action in ECs by Ang II involves at least two primary
line with evidence implicating excessive Ser phosphory- mechanisms. First, in cultured ECs, Ang II induces in-
lation of IRS-1 as a key mechanism underlying cellular sulin resistance via activation of numerous Ser kinases,
insulin resistance (33). Aldosterone-induced activation of including Jun NH -terminal kinase, MAPK, and p70 S6
2
Src and ROS production can also activate both redox- kinase1,leadingtoincreasedSerphosphorylationofIRS-1
sensitive and -insensitive Ser kinases, including p70 S6 and impaired insulin signaling via PI3K (33). Second, Ang
kinase 1, Rho kinase, and protein kinase C, among others II, like aldosterone, is a potent stimulator of ROS pro-
(34). Aldosterone has been linked to ROS-dependent acti- ductionandelevationsinECoxidativestressactindirectly
vation of Rho kinase in VSMCs (35) and p70 S6 kinase toreduceinsulinactionbyreducinginsulin-stimulatedNO
activation in proximal tubule and glomerular mesangial bioavailability and vasodilation (33). These data suggest
cells (36). Thus, it is likely that MR signaling activates that parallels may exist between MR-mediated insulin re-
multiple kinases directly or indirectly via ROS production sistance in ECs and VSMCs, particularly as they relate to
and changes in cellular redox state leading to increased the role of Ser kinases. Further studies are necessary,
IRS-1 Ser phosphorylation, reduced IRS-1 tyrosine phos- however, to directly examine the role of aldosterone and
phorylation, and subsequent attenuation of vascular in- MRsignalinginthemodulationofECinsulinsignalingand
sulin signaling. Future work is necessary to elucidate the sensitivity and whether the benefit of MR blockade on EC
specific kinases involved in aldosterone-induced IRS-1 function in diabetes involves restoration of EC insulin
degradation in VSMCs. signaling.
Amorerecentinvestigationdemonstrated,usingbothin
vivo and in vitro techniques, that aldosterone-induced
vascularinsulinresistanceinvolvesupregulationofIGF-1R ALDOSTERONE,INSULIN,ANDATHEROSCLEROSIS
and the hybrid insulin/IGF-1R receptor in VSMCs (Fig. 1) Although the role of aldosterone-induced vascular in-
(32). Specifically, these data showed that MR- and ROS- sulin resistance in atherosclerosis has not been directly
dependentupregulationofthesereceptorsaggravatesinvivo explored, overlapping pathways are dysregulated in the
316 DIABETES,VOL.62,FEBRUARY2013 diabetes.diabetesjournals.org
S.B.BENDERANDASSOCIATES
setting of vascular insulin resistance and vascular MR advanced atherosclerotic lesions (47). Conversely, over-
activation, thus supporting a potential molecular link expression of IGF-1 specifically in VSMCs in a hyper-
(Fig. 2). Atherosclerosis is a chronic inflammatory con- lipidemic mouse did not alter plaque size but produced
dition of the vasculature characterized by the formation plaques with increased VSMCs and decreased necrotic
of lipid-laden plaques in the arterial circulation. Unstable core, consistent with resistance to rupture (48). However,
plaques, characterized by increased inflammatory cells the relevance of this overexpression model requires fur-
and a necrotic core with a decreased VSMC cap, are ther investigation. Further work is necessary given recent
prone to rupture, resulting in acute vascular thrombosis data that IGF-1/IGF-1R signaling prevents pathologic
and occlusion, the root cause of most heart attacks and VSMCdedifferentiation,therebyincreasingplaquestability
strokes. (49). Overall, the proatherogenic effects of IGF-1R signal-
Available evidence demonstrates that MR activation ing (whether activated by insulin or IGF-1) appear to
promotes a proatherogenic vascular phenotype, particu- proceed predominantly through reduced NO bioavailabi-
larly with regard to the early stages of atherosclerosis. lity and increased inflammatory cell adhesion in ECs (50).
Atherogenesis initiates with EC dysfunction characterized As both diabetes and hyperaldosteronism predispose to
bydecreasedNOproduction,increasedvascularROS,and cardiovascular ischemia, it seems that in the setting of
enhanced EC adhesion molecule expression with subse- advanced EC dysfunction, such as with insulin resistance
quent inflammatory cell recruitment and VSMC hypercon- and MR activation, the proatherosclerotic effects of in-
tractility and proliferation. In ECs, aldosterone-induced sulin/IGF-1/IGF-1R signaling dominate to promote lesion
MR activation increases expression of intracellular cell development, inflammation, and plaque instability. Thus,
adhesion molecule 1 (ICAM-1) and the NADPH oxidase althoughadirectlinkamongvascularMRsignaling,insulin
Nox4, thereby promoting oxidative stress and decreased resistance, and atherosclerosis has yet to be established,
NO bioavailability (3,11). In addition, specific deletion of vascular insulin resistance and vascular MR regulate
SMCMRwasrecentlyshowntodecreaseROSproduction overlapping pathways that promote inflammatory athero-
and agonist-mediated vasoconstriction in aged mice (14). sclerosis with unstable plaque morphology that would pre-
Inanimalmodelsofatherosclerosis,aldosteroneenhances disposetoplaquerupture,heartattack,andstroke(Fig.2).
plaque burden via increased ROS generation due, in part,
to macrophage NADPH oxidase (reviewed in Ref. 3). In
SUMMARY
addition, in a mouse model with genetic deletion of the
cortisol-inactivating enzyme 11-b-hydroxysteroid dehydro- It is now clear that MR antagonists are protective in mul-
tiple CVD states. Moreover, the relationship between
genasetype2,chronicMRactivationbycortisolresultedin
obesity and plasma aldosterone supports a role for MR
increasedatheroscleroticlesionsizewithincreasedplaque
inflammation, although this mouse model is complicated activation as an early insult in obesity and overnutrition-
related vascular dysfunction and disease. Specifically, MR
by associated hypertension (40). Overall, MR activation
activationinVSMCsinducesvascularinsulinresistanceand
promotesvascularendothelialdysfunction,oxidativestress
and inflammation, and the formation of unstable athero- downstream signaling defects characteristic of obesity-
related vascular dysfunction. Importantly, evidence sug-
sclerotic plaques that are prone to rupture. Inhibition of
gests that vascular insulin resistance may be an early and
these processes may be responsible for the cardiovascular
benefits observed with MR antagonism (41). primary defect in vascular dysfunction. The role of MR ac-
tivation to induce EC insulin resistance remains largely
Impairedinsulinsignalingalsopromotesatherosclerosis
unstudied but warrants further investigation, as does the
by overlapping mechanisms; however, hyperinsulinemia
alone is not sufficient to drive plaque formation (Figs. 1 roleof MR-induced vascularinsulin resistanceinlong-term
vascular complications such as atherosclerosis. Promising
and 2) (42). Thus, aldosterone-mediated systemic insulin
avenues of future investigation regarding the interaction
resistance and the resultant hyperinsulinemia may act in
between MR and insulin signaling in vascular tissues in-
concert to promote atherogenesis. Accordingly, impaired
cludeMR-dependentactivationofSerkinasesandIRS-1Ser
insulin signaling combined with severe dyslipidemia in-
phosphorylation,aswellasthedelineationofMReffectson
creases atherosclerosis by inhibiting endothelial NO syn-
insulin–IGF-1 signaling. Furthermore, future studies should
thaseactivationandincreasingECexpressionofadhesion
addressthe temporalrelationshipbetween vascular insulin
molecules (43). Overlapping effects of insulin and MR on
resistance and overt vascular dysfunction in CVD states.
several vascular signaling cascades further support a link
Furtherexplorationoftheseareashasthepotentialtoyield
in the pathogenesis of atherosclerosis. In human VSMCs,
noveltreatmenttargetstopreventvasculardysfunctionand
insulin increases AT1R expression similar to reported
CVDinthegrowingpopulationofhigh-riskindividualswith
effects of MR activation in disease states (44). Insulin-
obesity and diabetes.
induced upregulation of the AT1R is more pronounced in
cells isolated from patients with type 2 diabetes and pre-
cedes diabetes-induced plaque formation and inflam- ACKNOWLEDGMENTS
mation (44,45), implicating RAAS activation in the early This work was supported by grants from the National
stages of insulin resistance-associated atherosclerosis. In Institutes of Health (HL-073101 and HL-107910 to J.R.S.
addition, as discussed above, aldosterone enhances hy- and HL-095590 to I.Z.J.) and the Veterans Affairs Merit
pertrophicinsulinsignaling,inpart,viaupregulationofthe System (0018 to J.R.S.).
hybrid insulin/IGF-1R (32), suggesting a shift in the pre- No potential conflicts of interest relevant to this article
dominant cascades activated by insulin from anti- to pro- were reported.
atherogenic. This is consistent, in large part, with reports S.B.B., A.P.M., I.Z.J., and J.R.S. researched, wrote, and
of proatherogenic IGF-1 signaling in disease states. edited the manuscript.
Cholesterol-fed rabbits administered IGF-1 develop larger The authors are grateful for the assistance of Brenda
and more inflamed atherosclerotic plaques (46), and cir- Hunter and Stacy Turpin at the University of Missouri in
culatingIGF-1levelsareelevatedinpatientswithcomplex, manuscript and figure preparation, respectively.
diabetes.diabetesjournals.org DIABETES,VOL.62,FEBRUARY2013 317
MR-MEDIATEDVASCULARINSULINRESISTANCE
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