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Heart Failure and Memory Loss: Is Angiotensin II the Missing Link?



Review of “Angiotensin II Causes Apoptosis of Adult Hippocampal Neural Stem Cells and Memory Impairment through the Action on AMPK-PGC1α Signaling in Heart Failure” from STEM CELLS Translational Medicine by Stuart P. Atkinson

Memory loss represents a significant comorbidity associated with heart failure [1, 2]; however, we currently lack a detailed description of any link between these two pathologies. Now, the laboratories of Seong Who Kim (University of Ulsan) and Yunhee Kim Kwon (Kyunghee University, Seoul, Korea) have discovered that the hormone system that regulates plasma sodium concentration and arterial blood pressure [3] may influence memory loss by affecting adult neurogenesis in brain regions linked to memory processing [4]. 

Has this new STEM CELLS Translational Medicine study finally uncovered the missing link between heart failure and memory loss [5]?

Specifically, Kim et al. set out to explore how angiotensin II (Ang II) may affect neurogenesis of hippocampal neural stem cells (HCNs), given previous promising studies [3]. In fact, the team discovered that elevated levels of Ang II decreased HCN proliferation in vitro and induced cell death via the production of mitochondrial reactive oxygen species (ROS). Higher ROS levels activated AMP-activated protein kinase (AMPK) signaling (a known sensor of energy balance), which then induced peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) expression and cell death through a Bax-associated pathway [6].

However, in vivo analysis discovered that heart failure-associated induction of Ang II contributed to memory loss and the death of newly born neural cells produced by HCNs (as measured by TUNEL – See Figure), but not HCNs themselves. However, treatment of HF-model mice with an Ang II receptor blocker reversed symptoms and therefore, this strategy may represent an exciting means to reduce memory loss following HF in human patients.

This new study suggests that Angiotensin II represents the “missing link” between heart failure and memory loss and highlights a possible means, via Ang II receptor blockers, to remedy this damaging comorbidity. However, the authors note some limitations to their study which the hope to assess in the future. These include additionally studying the modulation of HCN function and/or memory by differential blood flow and pressure, comparing differential effects of systemic or local Ang II, and assessing modifications to other brain regions.

Keep tuned to the Stem Cells Portal for more news on this newly discovered missing link!


  1. McLennan SN, Pearson SA, Cameron J, et al. Prognostic importance of cognitive impairment in chronic heart failure patients: does specialist management make a difference? Eur J Heart Fail 2006;8:494-501.
  2. Dekker RL, Moser DK, Peden AR, et al. Cognitive therapy improves three-month outcomes in hospitalized patients with heart failure. Journal of cardiac failure 2012;18:10-20.
  3. Inaba S, Iwai M, Furuno M, et al. Continuous activation of renin-angiotensin system impairs cognitive function in renin/angiotensinogen transgenic mice. Hypertension 2009;53:356-362.
  4. Gage FH, Coates PW, Palmer TD, et al. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc Natl Acad Sci U S A 1995;92:11879-11883.
  5. Kim M-S, Lee G-H, Kim Y-M, et al. Angiotensin II Causes Apoptosis of Adult Hippocampal Neural Stem Cells and Memory Impairment Through the Action on AMPK-PGC1α Signaling in Heart Failure. STEM CELLS Translational Medicine 2017;6:1491-1503.
  6. D'Errico I, Lo Sasso G, Salvatore L, et al. Bax is necessary for PGC1alpha pro-apoptotic effect in colorectal cancer cells. Cell Cycle 2011;10:2937-2945.