Atherosclerosis
is a chronic disease affecting large arteries that involves the
formation of plaques containing vascular and inflammatory cells, lipids
and extracellular matrix [
1].
Its clinical complications arise from luminal obstruction due to plaque
growth leading to
vessel stenosis, and/or formation of
unstable plaques
that acutely rupture leading to an
occlusive thrombus formation [
2].
Vascular smooth muscle cells (VSMCs) play a main role in this process
as they contribute to plaque growth in early stages, but favor plaque
stability in advanced stages of atherogenesis [
3].
- SUOMENNOSTA:
- Insuliinin (Ins) ja insuliininkaltaisten kasvutekijöiden (IGFs) signalointi välittyy hormoni-interaktioilla ja reseptoreina toimivat insuliinireseptori (IR) ja IGF-I reseptori (IGF-IR), jotka ovat Tyrosiinikinaasireseptorien superperheen II-alaluokan jäseniä. Imettäväisissä alternatiivisella pleissauksellaa insuliinireseptorigeenistä tulee kaksi isoformia IR A ja IR B. IRB omaa 12 aminohapon lisäsekvenssin, jota koodaa exoni 11. Vaikka molemmat isoformit omaavat saman affiniteetin insuliinia kohtaan, niin IRA ilmentää suurempaa affiniteettia insuliininkaltaisia kasvutekijöitä ( IGFs) kohtaan, erityisesti IGF-II-muotoa kohtaan. Täten voidaan todeta,että IRB ensisijassa on assosioitunut metabolisiin ja differentioiviin signalointeihin, kun taas IRA pääasiassa suosii solukasvua, proliferaatiota ja elossapysymistä. Lisäksi IGF-II-muoto voi sitoutua omaan IGF-II-reseptoriin (IGF-IIR) suurella affiniteetilla.
- IGF-IIR on tyypiltään transmembraaninen glykoproteiini, jolla on suuri affiniteetti myös mannoosi-6-fosfaattiin, joten se voi sitoutua myös lysosomaalisiin entsyymeihin ja muihin kasvutekijöihin ja sytokiineihin. Sillä onkin hyvin dolumentoitu tehtävä solunsisäisessä lysosomaalisten entsyymien kuljetuksessa ja IGF-II:n puhdistamisessa verenkierrosta. Mutta IGF-IIR ei omaa tyrosiinikinaasiaktiivisuutta eikä se autofosforyloidukaan, vaan linkkiytyy G-proteiinivälitteisesti signaalin johtumisverkostoon ja täten voi osallistua solukäytöksen säätelyyn.
The
insulin and insulin-like growth factors (IGFs) signaling is mediated by
hormone interaction with the insulin receptor (IR) and the IGF-I
receptor (IGF-IR), which are members of subclass II tyrosine kinase
receptor super-family [
4,
5]. In mammals, alternative splicing of the IR gene gives rise to two isoforms:
IRA and IRB [6].
Indeed, IRB has an additional 12-amino acid sequence encoded by the
exon 11. Although
both isoforms have similar affinity for insulin, IRA
exhibits a higher affinity for IGFs, especially for IGF-II [7].
Thus, IRB is preferentially associated with metabolic and
differentiating signals, whereas IRA mainly favors cell growth,
proliferation and survival [8].
In addition to IR and IGF-IR, IGF-II binds IGF-II receptor (IGF-IIR)
with high affinity. IGF-IIR is a type I transmembrane glycoprotein that
also have high affinity for mannose-6-phosphate, and can therefore bind
lysosomal enzymes and other growth factors and cytokines [9].
It plays a well-documented role in the intracellular transport of
lysosomal enzymes and in clearance of IGF-II from the circulation.
However, although IGF-IIR contains neither tyrosine kinase activity nor
an autophosphorylation site, it does link to G-proteins providing a
mechanism for signal transduction that may be involved in cell behavior
regulation [10, 11].
In early atherosclerotic lesions, IGFs contribute to plaque growth by promoting VSMCs proliferation and migration [
12].
In this regard, we previously demonstrated that overexpression of
IGF-IR or IRA isoform during early atherosclerosis confers a
proliferative and migratory advantage to VSMCs favoring atherosclerotic
progression [
13,
14].
In advanced stages, the imbalance between cell death and survival may
substantially affect the cellularity and integrity of atherosclerotic
lesions contributing to plaque instability. Unstable plaques that are
prone to rupture have a thin fibrous cap with a decreased number of
VSMCs and a dense infiltration of inflammatory cells [
15,
16], as well as an increased apoptosis of VSMCs and macrophages [
17].
IGF-I, through IGF-IR, has been reported to prevent atherosclerotic
plaque instability by its mitogenic and antiapoptotic effects on VSMCs [
18,
19,
20].
However, the role of IR isoforms or IGF-IIR in VSMCs apoptosis and
thereby in plaque instability remains unknown. In the present study, we
analyzed the expression of IR isoforms, IGF-IR and IGF-IIR, as well as
VSMCs content in human carotid atherosclerotic plaques and in
experimental models of atherosclerosis. Finally, we assessed the
contribution of IR isoforms and IGF-IR to the apoptosis of murine aortic
VSMCs lines.
- SUOMENNOSTA TÄMÄN TUTKIMUKSEN TULOKSISTA.Komplisoiduissa ateroskleroottisissa plakeissa on havaittu, että IRA/IRB-suhde on laskenut ia IGF-IR on laskenut, IGF-IIR on lisääntynyt ja VSMC- vaskulaarisia sileitä lihassoluja on kadonnut.
Results
Decrease of IRA/IRB ratio and IGF-IR, increase of IGF-IIR, and loss of VSMCs in complicated human atherosclerotic plaques
