Apoptosis inhibitor attenuates cardiac ischemia/reperfusion injury‐induced amyloid beta aggregation and dendritic spine loss in rats

Abstract

Recently, several studies have reported the incidence of cognitive impairments in patients with acute myocardial infarction and heart failure. Mechanistically, dendritic spine loss in hippocampus, due to oxidative stress/inflammation induced apoptosis, is proposed as one of responsible mechanisms underlying cognitive impairments. However, the effects of z-vad, which is an apoptosis inhibitor, on brain pathologies following cardiac ischemia/reperfusion (I/R) injury have never been investigated. We hypothesized that z-vad alleviates brain damage in rats with cardiac I/R injury by reducing apoptosis, mitochondrial oxidative stress, and inflammation. Fifty-four male rats were subjected to either sham (n=6/group) or cardiac I/R operation (n=48). Rats in cardiac I/R group were divided into 4 groups (n=6-12/group) including 1) vehicle, 2) low-dose of z-vad (L-z-vad; 1.65 mg/kg), medium-dose of z-vad (M-z-vad; 3.3 mg/kg), and high-dose of z-vad (H-z-vad; 6.6 mg/kg). Treatments were intravenously injected to the rats at 15 min before ischemia. Then, rats were subjected to left anterior descending coronary artery ligation induced myocardial ischemia for 30 min, followed by 120 min of reperfusion. At the end of protocol, rats were sacrificed, and the brain was used to determine mitochondrial oxidative stress, inflammation, cell death pathways, blood brain barrier (BBB), Alzheimer's disease related proteins, and dendritic spine density. Cardiac I/R injury led to BBB breakdown, increased brain mitochondrial oxidative stress and apoptosis, as well as amyloid beta aggregation, tau hyperphosphorylation, and subsequent dendritic spine loss. Treatment with M-z-vad and H-z-vad reduced dendritic spine loss, tau hyperphosphorylation, and Bax/Bcl2 ratio. Additionally, the reduction of dendritic spine density was lowered in M-z-vad than H-z-vad group, since only M-z-vad attenuated mitochondrial oxidative stress, inflammation, amyloid beta aggregation, and cleaved-caspase 3 protein expression. For L-z-vad, we found that this treatment regimen showed no benefit on brain pathologies following cardiac I/R injury, implying that low dose of z-vad may be insufficient to exert neuroprotection (Figure 1). Moreover, all doses of z-vad did not decrease BBB breakdown after cardiac I/R injury. Pretreatment with medium dose of apoptosis inhibitor prevented amyloid beta aggregation and dendritic spine loss against cardiac I/R injury, possibly through reductions of mitochondrial oxidative stress, inflammation, and apoptosis.