Cardioprotective Effects of Cuminaldehyde Mitigate Isoproterenol‐Induced Myocardial Infarction by Modulating the PGC‐1α/ND2‐Mediated Mitochondrial and eNOS/NO/VCAM‐1‐ Mediated Endothelial Dysfunction Pathways

Mitochondrial and endothelial dysfunction play a crucial role in the progression of myocardial infarction(MI). In this study, we appraised the cardioprotective effects of cuminaldehyde, a monocyclic terpenoid, and its molecular mechanisms by analyzing novel peroxisome proliferator-activated receptor-gamma coactivator-1α(PGC-1α)/NADH-dehydrogenase 2 (ND2)-mediated mitochondrial and endothelial nitric oxide synthase (eNOS)/nitric oxide (NO)/vascular cell adhesion molecule-1(VCAM-1) mediated endothelial dysfunction pathways in isoproterenol-induced myocardial infarcted rats. MI was induced in rats by isoproterenol (100 mg/kg body weight). Then, cuminaldehyde (20 mg/kg body weight) was administered orally daily for 3 weeks, and parameters related to mitochondrial and endothelial dysfunction were evaluated. The findings of this study showed that after isoproterenol administration, serum cardiac sensitive markers and heart rate increased. Furthermore, lipid peroxidation products and calcium ions were elevated, whereas antioxidants, isocitrate dehydrogenase, malate dehydrogenase, α-ketoglutarate dehydrogenase, NADH dehydrogenase, cytochrome c oxidase and adenosine triphosphate were decreased in isoproterenol-induced heart mitochondria. The transmission electron microscopic study validated mitochondrial damage. RT-PCR revealed reduced myocardial expression of PGC-1α and ND2. Moreover, the MI group showed lowered plasma NO, and the ELISA study revealed reduced eNOS and enhanced VCAM-1 in serum. The myocardial eNOS expression was diminished, and myocardial VCAM-1 expression was increased by RT-PCR. Histopathological findings revealed myocardial damage. Nevertheless, cuminaldehyde decreased cardiac diagnostic markers, heart rate, lipid peroxidation products, calcium ions, VCAM-1, and increased antioxidant system, mitochondrial enzymes, adenosine triphosphate, PGC-1α, ND2, NO, eNOS, and preserved mitochondrial and heart tissue architecture. Thus, cuminaldehyde modulated PGC-1α/ND2 and eNOS/NO/VCAM-1 pathways and alleviated mitochondrial and endothelial dysfunction, thereby mitigating MI in isoproterenol-induced rats and protecting the heart, by its anti-mitochondrial and anti-endothelial dysfunction mechanisms.