Acute insulin resistance stimulates and insulin sensitization attenuates vascular smooth muscle cell migration and proliferation

Eugenio Cersosimo, Xiaojing Xu, Sikarin Upala, Curtis L Triplitt, Nicolas Musi

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Abstract

Differential activation/deactivation of insulin signaling, PI-3K and MAP-K pathways by high glucose and palmitate, with/out the insulin sensitizer pioglitazone (PIO), have been previously shown in vascular smooth muscle cells (VSMCs). To determine the biological impact of these molecular changes, we examined VSMC migration and proliferation ("M"&"P") patterns in similar conditions. VSMCs from healthy human coronary arteries were incubated in growth medium and "M"&"P" were analyzed after exposure to high glucose (25 mmol/L) ± palmitate (200 µmol/L) and ± PIO (8 µmol/L) for 5 h. "M"&"P" were assessed by: (1) polycarbonate membrane barrier with chemoattractants and extended cell protrusions quantified by optical density (OD595 nm); (2) % change in radius area (2D Assay) using inverted microscopy images; and (3) cell viability assay expressed as cell absorbance (ABS) in media. "M" in 25 mmol/L glucose media increased by ~25% from baseline and % change in radius area rose from ~20% to ~30%. The addition of PIO was accompanied by a significant decrease in "M" from 0.25 ± 0.02 to 0.19 ± 0.02; a comparable decline from 0.25 ± 0.02 to 0.18 ± 0.02 was also seen with 25 mmol/L of glucose +200 µmol/L of palmitate. When PIO was coincubated with high glucose plus palmitate there was a 50% reduction in % change in radius. A ~10% increase in ABS, reflecting augmented "P" in media with 25 mmol/L glucose versus control was documented. The addition of PIO reduced ABS from 0.208 ± 0.03 to 0.183 ± 0.06. Both high glucose and palmitate showed ABS of ~0.140 ± 0.02, which decreased with PIO to ~0.120 ± 0.02, indicating "P" was reduced. Conclusion: These results confirm that high glucose and palmitate stimulate VSMCs migration and proliferation in vitro, which is attenuated by coincubation with the insulin sensitizer PIO. Although, we cannot ascertain whether these functional changes are coincident with the activation/deactivation of signal molecules, our findings are consistent with the theory that differential regulation of insulin signaling pathways in VSMCs in insulin-resistant states plays an important role in inflammation, arterial wall thickening, and plaque formation during development of atherosclerosis.

Original languageEnglish (US)
Article numbere12123
JournalPhysiological Reports
Volume2
Issue number8
DOIs
StatePublished - 2014

Fingerprint

pioglitazone
Vascular Smooth Muscle
Smooth Muscle Myocytes
Cell Movement
Insulin Resistance
Palmitates
Cell Proliferation
Insulin
Glucose
polycarbonate
Arteritis
Chemotactic Factors
Phosphatidylinositol 3-Kinases
Microscopy
Cell Survival
Atherosclerosis
Coronary Vessels

Keywords

  • Cell proliferation
  • Hyperinsulinemia
  • Inflammation
  • Insulin signaling
  • Migration
  • Vascular dysfunction
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Physiology (medical)
  • Physiology

Cite this

Acute insulin resistance stimulates and insulin sensitization attenuates vascular smooth muscle cell migration and proliferation. / Cersosimo, Eugenio; Xu, Xiaojing; Upala, Sikarin; Triplitt, Curtis L; Musi, Nicolas.

In: Physiological Reports, Vol. 2, No. 8, e12123, 2014.

Research output: Contribution to journalArticle

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AU - Xu, Xiaojing

AU - Upala, Sikarin

AU - Triplitt, Curtis L

AU - Musi, Nicolas

PY - 2014

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N2 - Differential activation/deactivation of insulin signaling, PI-3K and MAP-K pathways by high glucose and palmitate, with/out the insulin sensitizer pioglitazone (PIO), have been previously shown in vascular smooth muscle cells (VSMCs). To determine the biological impact of these molecular changes, we examined VSMC migration and proliferation ("M"&"P") patterns in similar conditions. VSMCs from healthy human coronary arteries were incubated in growth medium and "M"&"P" were analyzed after exposure to high glucose (25 mmol/L) ± palmitate (200 µmol/L) and ± PIO (8 µmol/L) for 5 h. "M"&"P" were assessed by: (1) polycarbonate membrane barrier with chemoattractants and extended cell protrusions quantified by optical density (OD595 nm); (2) % change in radius area (2D Assay) using inverted microscopy images; and (3) cell viability assay expressed as cell absorbance (ABS) in media. "M" in 25 mmol/L glucose media increased by ~25% from baseline and % change in radius area rose from ~20% to ~30%. The addition of PIO was accompanied by a significant decrease in "M" from 0.25 ± 0.02 to 0.19 ± 0.02; a comparable decline from 0.25 ± 0.02 to 0.18 ± 0.02 was also seen with 25 mmol/L of glucose +200 µmol/L of palmitate. When PIO was coincubated with high glucose plus palmitate there was a 50% reduction in % change in radius. A ~10% increase in ABS, reflecting augmented "P" in media with 25 mmol/L glucose versus control was documented. The addition of PIO reduced ABS from 0.208 ± 0.03 to 0.183 ± 0.06. Both high glucose and palmitate showed ABS of ~0.140 ± 0.02, which decreased with PIO to ~0.120 ± 0.02, indicating "P" was reduced. Conclusion: These results confirm that high glucose and palmitate stimulate VSMCs migration and proliferation in vitro, which is attenuated by coincubation with the insulin sensitizer PIO. Although, we cannot ascertain whether these functional changes are coincident with the activation/deactivation of signal molecules, our findings are consistent with the theory that differential regulation of insulin signaling pathways in VSMCs in insulin-resistant states plays an important role in inflammation, arterial wall thickening, and plaque formation during development of atherosclerosis.

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KW - Hyperinsulinemia

KW - Inflammation

KW - Insulin signaling

KW - Migration

KW - Vascular dysfunction

KW - Vascular smooth muscle cells

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