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Published on: June 3, 2018
IGF-1 regulates cardiac fibroblast apoptosis induced by osmotic stress
J W Mockridge1, E C Benton, L V Andreeva
1Department of Cardiology, St. Thomas' Hospital, London, SE1 7EH, United Kingdom. james.mockridge@kcl.ac.uk
Abstract:
In this study we have determined the ability of IGF-1 to protect cardiac fibroblasts against osmotic-induced apoptosis and investigated the potential mechanism(s) underlying this protection. Treatment with IGF-1 (1-100 ng/ml) promoted a dose dependent increase in cell survival against osmotic cell death. Both Akt and ERK1/2 were rapidly phosphorylated by IGF-1 and blocked by wortmannin and PD98059, inhibitors of their upstream activators respectively. However, IGF-1-induced protection was mediated via a wortmannin-dependent but PD98059-independent pathway as determined by cell survival assay suggesting a role of PI3-K/Akt. Furthermore, IGF-1 appeared to reduce the activation of a number of early components in the apoptotic pathway in a wortmannin dependent manner including the osmotic stress-induced perturbation in mitochondrial membrane potential, cleavage and activation of caspase-3 and DNA fragmentation. Thus, the results suggest that IGF-1 regulates osmotic stress-induced apoptosis via the activation of the PI3-K/Akt pathway at a point upstream of the mitochondria and caspase-3.
Insights
Insulin-like growth factor-1 (IGF-1) protects cardiac fibroblasts from cell death by activating the PI3-K/Akt pathway. This pathway regulates apoptosis upstream of mitochondria and caspase-3 activation.
Area of Science:
- Cardiology
- Cell Biology
- Molecular Biology
Background:
- Cardiac fibroblasts are crucial for heart tissue integrity.
- Osmotic stress can induce apoptosis in cardiac cells, contributing to cardiac dysfunction.
- Understanding protective mechanisms is vital for developing therapeutic strategies.
Purpose of the Study:
- To determine if Insulin-like Growth Factor-1 (IGF-1) protects cardiac fibroblasts from osmotic stress-induced apoptosis.
- To investigate the molecular mechanisms underlying IGF-1's protective effects.
Main Methods:
- Cardiac fibroblasts were treated with varying concentrations of IGF-1.
- Cell survival assays were performed following osmotic stress.
- Western blotting was used to assess the phosphorylation of Akt and ERK1/2.
- Inhibitors wortmannin (PI3-K inhibitor) and PD98059 (MEK inhibitor) were utilized.
- Mitochondrial membrane potential, caspase-3 activation, and DNA fragmentation were analyzed.
Main Results:
- IGF-1 demonstrated a dose-dependent increase in cardiac fibroblast survival against osmotic stress.
- IGF-1 rapidly phosphorylated both Akt and ERK1/2.
- IGF-1-mediated cell protection was dependent on PI3-K/Akt pathway activation (wortmannin-sensitive) but independent of ERK1/2 activation (PD98059-insensitive).
- IGF-1 attenuated osmotic stress-induced mitochondrial dysfunction, caspase-3 activation, and DNA fragmentation in a wortmannin-dependent manner.
Conclusions:
- IGF-1 protects cardiac fibroblasts against osmotic stress-induced apoptosis.
- The protective mechanism involves the activation of the phosphoinositide 3-kinase (PI3-K)/Akt pathway.
- This pathway acts upstream of mitochondrial perturbations and caspase-3 activation in the apoptotic cascade.
