Lack of insulin receptor substrate-2 causes progressive neointima formation in response to vessel injury.
BACKGROUND
Insulin resistance is associated with atherosclerosis, but its mechanism is unknown. It has been reported that insulin receptor substrate (IRS)-1 deficient (IRS-1-/-) mice showed insulin resistance without type 2 diabetes, whereas the IRS-2 deficient (IRS-2-/-) mice showed insulin resistance with type 2 diabetes.


RESULTS
We investigated neointima formation in the IRS-1-/- and IRS-2-/- mice at 8 and 20 weeks. The IRS-2-/- mice showed much greater neointima formation than the IRS-1-/- and wild-type mice at 8 weeks. At 20 weeks, the IRS-2-/- mice had greater neointima formation than the IRS-1-/- mice, which showed more enhanced neointima formation than the wild-type mice. The IRS-1-/- and IRS-2-/- mice had dyslipidemia, hypertension, and insulin resistance. The IRS-2-/- mice had more metabolic abnormalities than the IRS-1-/- mice at 8 and 20 weeks. IRS-2 expression was detected, but IRS-1 expression was not detected in the vessels.


CONCLUSIONS
The neointima formation in the IRS-1-/- and IRS-2-/- mice appears to be related to abnormalities induced by the altered metabolic milieu in insulin-resistant states. Moreover, because neointima formation was much greater in the IRS-2-/- mice than in the IRS-1-/- mice at 8 and 20 weeks, it is suggested that a lack of IRS-2 renders the vasculature more susceptible to injury in the abnormal metabolic milieu, and IRS-2 may have a protective effect on neointima formation. We conclude that IRS-2 is protective and retards the development of neointima formation in insulin-resistant states.
Kubota
Tetsuya
T
Third Department of Internal Medicine, Toho University School of Medicine, Ohashi Hospital 2-17-6 Ohashi, Meguro-ku, Tokyo 153-8515, Japan.
Kubota
Naoto
N
Moroi
Masao
M
Terauchi
Yasuo
Y
Kobayashi
Tsuneo
T
Kamata
Katsuo
K
Suzuki
Ryo
R
Tobe
Kazuyuki
K
Namiki
Atsushi
A
Aizawa
Shinichi
S
Nagai
Ryozo
R
Kadowaki
Takashi
T
Yamaguchi
Tetsu
T
D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005263:Femoral Artery / Q000293:injuries / Q000473:pathology; D006946:Hyperinsulinism / Q000097:blood / Q000235:genetics; D006949:Hyperlipidemias / Q000473:pathology / Q000503:physiopathology; D006973:Hypertension / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood; D017539:Tunica Intima / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D014654:Vascular Patency; D014664:Vasodilation / Q000235:genetics
D005230:Fatty Acids, Nonesterified; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D014280:Triglycerides