Table S1: Summary of publications supporting pro-survival, pro-death or dual theories of HIF-1α in non-neuronal and neuronal tissues

In non-neuronal tissues, the “pro-survival” effect of HIF-1α is predominant as reported in the majority of studies (Bosch-Marce et al., 2007; Rey et al., 2009; Rey et al., 2011; Schito and Semenza, 2016; Semenza, 2010). Notably, the measurement of these experiments was focused on response to the environment, such as adaptation of cancer cells to low oxygen or angiogenesis to restore oxygen supply for survival.

However, the assessment of HIF-1α in ischemic brains has been based on infarct size, not the environment. Thus, both “pro-death” and “pro-survival” theories are reported in the literature. The “pro-death” effect of HIF-1α is supported by acute experiments (<24h after ischemia) (Barteczek et al., 2017; Cheng et al., 2014; Liu et al., 2015; Yang et al., 2017), which is consistent with the timing in our study. In contrast, the “pro-survival” effect of HIF-1α is mainly supported by later assessments on infarct size (>4 d after ischemia) (Baranova et al., 2007; Bergeron et al., 2000; Kunze et al., 2012; Sheldon et al., 2014; Sheldon et al., 2009). However, these studies have overlooked the contribution of brain plasticity to infarct size at later time points.

Table S1.1: Pro-Survival

Tissue Model Timing of Outcome Measurement

Neonatal Brain(Bergeron et al., 2000; Sheldon et al., 2014; Sheldon et al., 2009)

Preconditioning followed by Ischemia in neuron-specific HIF-/- mice

5 day-1 week

Adult Brain (Baranova et al., 2007)

(Kunze et al., 2012)

Ischemia in neuron-specific HIF-/-

Ischemia in PHD-/-

4 days

Non-Neuronal Tissue

Vascular System(Bosch-Marce et al., 2007) (Rey et al., 2009; Rey et al., 2011)

Limb Ischemia Angiogenic Effect at 3 days

Cancer Cells(Schito and Semenza, 2016; Semenza, 2010)

Various Cancer Types Chronic Adaptation

Table S1.2: Pro-Death

Tissue Experiments Timing of Outcome Measurement

Adult Brain(Barteczek et al., 2017; Cheng et al., 2014; Liu et al., 2015; Yang et al., 2017)

Acute Ischemia in neuron-specific HIF-/-, RNA interference or inhibitors of HIF-1α

Immediately after insult

Table S1.3: Dual Effects

Tissue Model Timing of Outcome Measurement

Neuronal Cell Line(Aminova et al., 2005)

Neonatal Brain(Chen et al., 2009)

Oxidative Stress and DNA Damage

Review

12-16 h

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