Abstract 12525: The Role of Angiotensin II on Survival and Function of Adult Hippocampal Neural Stem Cells as a Cause of Cognitive Impairment in Heart Failure
Background: Cognitive impairment is relatively common and associated with poor prognosis in patients with heart failure (HF). However, there were few data about underlying mechanism of cognitive impairment. We hypothesized that angiotensin II (Ang II), which is a key neurohumoral cytokine for the progression of HF, would reduce survival and function of adult hippocampal neural (HCN) stem cell which would be a cause of cognitive dysfunction in HF.
Methods and Results: HCNs were derived from the adult rat brain. RT-PCR showed the expression of Ang II type 1 and 2 receptors in HCNs. The proliferation of HCNs was measured using BrdU cell proliferation assay. Ang II reduced proliferative activity of HCNs in a dose- and time-dependent manner. Next, propidium iodide staining and trypan blue exclusion test were performed for cell viability. Ang II (1 uM) treatment for 48 hours induced HCN death (viable cells; 71.6% and 71.2%, compared with control, p≤0.05, respectively). To understand the type of cell death in HCNs following Ang II treatment, western-blotting was used. DNA fragmentation or caspase-3 activation was not observed, but rather dying cells displayed features of autophagy, including increased expression of Beclin 1 and the type II form of light chain 3. Electron micrographs showed the increased formation of autophagic vacuoles with cytoplasmic contents. Autophagic cell death was suppressed by a selective angiotensin receptor blocker (Losartan). To investigate the effect of Ang II-mediated HCN regulation on cognitive function in a HF rat model, we performed the Morris water maze test. The escape latency was longer in HF group than in sham or control groups (33.1±2.3 vs 18.2±3.4 vs 16.9±3.8 seconds, p≤0.05, respectively). BrdU-labeled cells merged with nestin, a marker of HCN, were quantified in the hippocampal granule cell layer. The number of co-merged cells was significantly decreased in HF group (12±2 vs 45±3 vs 50±4 cells/mm2, p≤0.05, respectively).
Conclusion: We demonstrated that Ang II lead to autophagic HCN death, and this was associated with cognitive dysfunction in a HF rat model. These finding suggests that HCN is a treatment target for cognitive impairment in HF and Ang II blockers with more penetration into the brain should be used for better outcomes.
- © 2013 by American Heart Association, Inc.