Abstract
Cognitive impairment has been reported in patients with myocardial infarction despite a successful reperfusion therapy. Several modes of cell death are involved in brain damage during cardiac ischemia/reperfusion (I/R) injury. Although apoptosis, necroptosis, and ferroptosis inhibitors provided neuroprotection against cerebral I/R injury, the effects of these cell death inhibitors on the brain following cardiac I/R injury have never been investigated. We hypothesized that apoptosis, necroptosis, and ferroptosis inhibitors attenuate brain damage following cardiac I/R injury. One-hundred and twenty-six male rats were used: 6 rats were assigned to sham operation and 120 rats were subjected to 30-min regional cardiac ischemia and 120-min reperfusion. Rats in cardiac I/R group were pretreated with either vehicle (n = 12) or one of cell death inhibitors. Rats treated with apoptosis, necroptosis, or ferroptosis inhibitor were subdivided into three different doses including low (L), medium (M), and high (H) doses (n = 12/group). Z-VAD, necrostatin-1 (Nec-1), and ferrostatin-1 (Fer-1) were used as apoptosis, necroptosis, and ferroptosis inhibitor, respectively. Rats were sacrificed at the end of reperfusion, and the brain was used to analyze dendritic spine density, Alzheimer’s disease (AD)-related proteins, blood–brain barrier (BBB) tight junction proteins, mitochondrial function, inflammation, and cell death. Our data showed that cardiac I/R led to brain damage and only apoptosis occurred in the hippocampus after cardiac I/R injury. In the cardiac I/R group, treatment with M-Z-VAD and all doses of Nec-1 decreased hippocampal apoptosis and amyloid beta aggregation, thereby reducing dendritic spine loss. M- and H-Fer-1 also reduced dendritic spine loss by suppressing ACSL4, TNF-α, amyloid beta, and tau hyperphosphorylation. Moreover, Bax/Bcl-2 was decreased in all treatment regimen except L-Z-VAD. Additionally, M-Z-VAD and M-Fer-1 partially attenuated mitochondrial dysfunction. Only L-Nec-1 preserved BBB proteins. In conclusion, cell death inhibitors prevented hippocampal dendritic spine loss caused by cardiac I/R injury through different mechanisms.
Highlights
Acute myocardial infarction (AMI) is a life-threatening cardiovascular disease caused by the blockage of coronary artery [1]
In the brain, we found that Nec-1 at all doses attenuated dendritic spine loss, and this beneficial effect was observed in medium-to-high-dose Z-VAD and Fer-1, when compared with the vehicle group (Fig. 1B)
The major findings of this study are as follows: (1) cardiac I/R injury causes brain damage as indicated by hippocampal dendritic spine loss, brain mitochondrial dysfunction, blood–brain barrier (BBB) breakdown, and increased hippocampal Alzheimer’s disease (AD)-related proteins, (2) cardiac I/R injury induced only hippocampal apoptosis, while necroptosis and ferroptosis did not occur, (3) cell death inhibitors reduced dendritic spine loss independently of cardioprotective effects, (4) brain mitochondrial dysfunction was partially attenuated by apoptosis and ferroptosis inhibitors, (5) AD-related protein levels and tau hyperphosphorylation were suppressed by all cell death inhibitors, (6) BBB proteins were preserved by necroptosis inhibitor, and (7) hippocampal apoptosis was reduced by both apoptosis and necroptosis inhibitors
Summary
Acute myocardial infarction (AMI) is a life-threatening cardiovascular disease caused by the blockage of coronary artery [1]. Reperfusion therapy, a standard treatment of AMI, can be achieved by primary percutaneous intervention or fibrinolytic therapy [1]. Adverse sequelae still occurred in the AMI patients despite a successful reperfusion [1]. In addition to cardiac complications, cognitive impairment has been reported in AMI patients [2]. Preclinical data from cardiac ischemia/reperfusion (I/R) injury model revealed that dendritic spine loss occurred in the brain [3, 4], making it incapable of forming a synapse to maintain normal cognition. Blood–brain barrier (BBB) breakdown is found in the model of cardiac I/R injury [3,4,5]. The disrupting of BBB allows circulatory inflammation and oxidative stress to get into the brain [6], potentiating further brain damage
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