Table 2.
Effects of HNE on vascular smooth muscle cells.
| Cell type | [HNE] μmol/L | Time | Findings | References |
|---|---|---|---|---|
| RTK, MAPK and PI3K/Akt activation | ||||
| MASMC | 0.1 | 10–90 min | In young but not aged animals↑p∼ERK1/2,↔p∼p38, p∼Jnk | [44] |
| RASMC | 1 | 5 min | ↑p∼ERK1/2 | [43] |
| HCSMC | 10 | 10 min | ↑p∼PDGFR, ↑p∼ERK1/2 | [40] |
| MASMC | 1 | 5–120 min | ↑p∼ERK1/2 that was maximal within 60 min,↑p∼p38 maximal within 30 min and p∼JNK reduced after 30 min of HNE treatment | [42] |
| RASMC | 1 | 5–120 min | Dose-dependent↑Akt activity | [41] |
| RASMC | 1 | 4 h | ↑PKC activation, abolished by AR inhibition | [45] |
| Proliferation | ||||
| RASMC | 0.1–1 | 12–24 h | Dose-dependent↑MMP-2 activity, mRNA and protein expression, which was dependent on Akt activation | [41] |
| MASMC | 1 | 24 h | ↑MMP-2 expression and activity which was dependent on HNE-induced ERK activation | [42] |
| MASMC | 0.1–10 | 24 h | 0.1 µM HNE ↑cell density in cells from young but not aged mice,↑ERK1/2 activation and downstream cyclin D1 mRNA expression. Higher doses 1–10 µM HNE↓cell density | [44] |
| 0.1 µM HNE ↑cell survival in cells from young but not aged mice. Aged cells showed↑ROS generation in response to HNE, with NAC↑survival in aged cell populations | ||||
| RASMC | 0.1–10 | 24 h | HNE and HNE conjugates (e.g. GS-HNE) <1 µM↑cell proliferation, with higher doses↓cell density. Aldose reductase activity required for cell survival/proliferation. Inhibition of HNE conjugate removal by RLIP76 transporter↑cell growth | [45] |
| HCSMC | 2–20 | 24 h | Dose-dependent ↑MMP-1 requiring HNE-induced PDGFR and downstream ERK1/2 activation | [40] |
| RASMC | 1 | 48–72 h | ↑Cell proliferation, attenuated by growth factor PDGF receptor autoantibodies | [43] |
| RASMC | 2.5 | 48 h | ↑Proliferation | [74] |
| HASMC | 2.5 | 72 h | ↑Cell proliferation, dependent on aldose reductase activity | [29] |
| Transcriptional activity | ||||
| HASMC | 1 | 0.5–6 h | 30 min following HNE exposure↑IκBα phosphorylation without inducing IƙB degradation. ↑NFκB DNA binding was also increased from 30 min of HNE stimulation | [72] |
| RASMC | 1 | 4 h | ↑NFκB and AP-1 activation | [45] |
| RASMC | 1 | 12 h | ↑NFκB activity but no change in AP-1, c-jun or CREB activity. NFƙB activation was dependent on mitochondria derived superoxide mediated Akt activation which and proceeds MMP-2 expression | [41] |
| RVSMC | 0–5 | 24 h | Dose-dependent ↓NFκB activation, with 50 µM HNE shown to prevent LPS/IFN induced proteasomal IκBα degradation. Accordingly, HNE dose-dependently (0–5 µM) ↓LPS/IFN induced nitrite production, with doses >12.5 µM↓iNOS expression | [73] |
| RASMC | 1–10 | 3 h | ↑Elk1, c-jun, CHOP and AP-1 activity, ↑c-jun and c-fos mRNA | [74] |
| RASMC | 2.5 | 1–2 h | ↑c-fos and c-jun expression, ↑AP-1 DNA binding | [43] |
| MASMC | 20 | 0–5 h | ↑Nrf2 nuclear accumulation and downstream HO-1, Prx1 and A170 mRNA, absent in cells derived from Nrf2 knockout mice | [54] |
| Phase II metabolism | ||||
| HASMC | 0.05 | 30 min | ↑Aldose reductase metabolized GSH conjugates | [29] |
| 2.5 | 8–12 h | ↑Aldose reductase mRNA (8 h) and protein (12 h) expression | ||
| RASMC | 1 | 5 min | ↓Cellular thiol content | [43] |
| RVSMC | 5–10 | 0–24 h | ↑Aldose reductase mRNA (7 h), protein (12 h) and activity (12–24 h) | [28] |
| RASMC | 0.1–10 | 24 h | HNE and HNE conjugates (e.g. GS-HNE) <1 µM↑cell proliferation, with higher doses↓cell density. Aldose reductase activity required for cell survival/proliferation. Inhibition of HNE conjugate removal by RLIP76 transporter↑cell growth | [45] |
| Oxidative stress and protein adduct clearance | ||||
| HASMC | 1 | 0–12 h | ↑8-isoprostane induced following 9 h HNE treatment | [72] |
| RASMC | 50 | 30 min | ↑Autophagy but not proteasomal HNE degradation | [15] |
| RVSMC | 50 | 4 h | ↓LPS/IFN induced proteasomal IƙBα degradation | [73] |
| RBASMC | 0–3000 | 4.5 h | ↓Recognition and clearance of LDL with increasing [HNE] | [12] |
| Cellular dysfunction | ||||
| PBMS | 10–100 | 0 min | ↓Carbachol induced relaxation | [148] |
| RVSMC | 0–5 | 24 h | HNE dose-dependently (0–5 µM) ↓LPS/IFN induced nitrite production, with doses >12.5 µM↓iNOS expression | [73] |
| Mitochondria | ||||
| RASMC | 1–30 | 10–60 min | HNE dose-dependently↑ROS production measured by DCF fluorescence with inhibitors of mitochondria abolishing HNE-induced superoxide generation | [96] |
| RASMC | 1 | 30 min | ↑Mitochondria derived superoxide | [41] |
| RASMC | 20 | 20–180 min | ↓Oxygen consumption rate (OCR),↔extracellular acidification rate (ECAR) | [97] |
| Apoptosis | ||||
| RASMC | 1–30 | 24 h | HNE >10 µM↑apoptosis, with 30 µM HNE also increasing necrosis | [44,96] |
| RVSMC | 5–15 | 6 h | HNE dose-dependently↑apoptosis, with AR inhibition↑HNE-induced apoptosis | [28] |
| HASMC | 0–100 | 6 h | 100 µM HNE induced DNA fragmentation | [72] |
Cell type abbreviations: HCSMC, human coronary smooth muscle cells; HASMC, Human aortic smooth muscle cells; RVMC, rat vascular smooth muscle cells; RASMC, rat aortic smooth muscle cells; RBASMC, rabbit aortic smooth muscle cells MASMC, mouse aortic smooth muscle cells; PBMS, pig bladder muscle strips.