Preclinical Evaluation of Berry Extracts as a Nutritional Intervention to Alleviate Myocardial Ischemia–Reperfusion Injury and Atherosclerosis Development

ABSTRACT Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. While studies suggest that berry fruits offer beneficial effects in CVD prevention, the bioactive compounds within different berries vary, and the specific mechanisms behind their protective effects are not yet fully elucidated. Our study aimed to evaluate and compare the cardioprotective and anti‐atherosclerotic effects of Morus alba (white mulberries, WMex) and Vaccinium myrtillus L. fruit extracts (blueberries, BBex), focusing on acute myocardial infarction (AMI), CVD risk factors, atherosclerosis development, and the underlying mechanisms. WMex and BBex were produced and their qualitative compositions were characterized. We evaluated the infarct size (IS) limiting potential of 8‐weeks supplementation with both WMex and BBex at nutritional doses in mice with western diet (WD)‐induced metabolic syndrome (MS). We further evaluated atherosclerosis development mitigation after 4‐weeks supplementation with the extracts in both male and female WD‐fed ApoE −/− mice as well as the putative cardioprotective and atheroprotective mechanisms. The total flavonoids in WMex and BBex were 49.50 and 98.92 mg rutin/g extract, respectively, while the total phenolic content was 50.74 and 110.00 mg gallic acid/g extract, respectively. Both extracts limited IS compared to Control by suppressing apoptosis. WMex upregulated endothelial nitric oxide synthase (eNOS) phosphorylation and pathway along with circulating nitrite levels. WMex suppressed the extent of atheromatic area in both male and female ApoE −/− mice, while BBex was effective in females without any of the extracts affecting estrogen levels. WMex downregulated NF‐kB‐ICAM‐1 axis in the atherosclerotic area and reduced circulating triglyceride levels. None of the extracts caused signs of toxicity, supporting a safety profile. In conclusion, WMex exerts potent cardioprotective and anti‐atherosclerotic properties in vivo and could be further exploited for CVD prevention.