Dl-3-n-butylphthalide protects the heart against ischemic injury and H9c2 cardiomyoblasts against oxidative stress: involvement of mitochondrial function and biogenesis

Abstract

BackgroundMyocardial infarction (MI) is an acute and fatal condition that threatens human health. Dl-3-n-butylphthalide (NBP) has been used for the treatment of acute ischemic stroke. Mitochondria may play a protective role in MI injury. However, there are few reports on the cardioprotective effect of NBP or the potential mitochondrial mechanism for the NBP-induced protection against cardiac ischemia injury. We investigated the therapeutic effects of NBP in an in vivo MI model and an in vitro oxidative stress model, as well as the potential mitochondrial mechanism.MethodsThis study comprised two different experiments. The aim of experiment 1 was to determine the protective effects of NBP on MI and the underlying mechanisms in vivo. In part 1, myocardial infarct size was measured by staining with 2,3,5-triphenyltetrazoliumchloride (TTC). Myocardial enzymes and mitochondrial enzymes were assayed. The aim of experiment 2 was to investigate the role of NBP in H2O2-induced myocardial ischemic injury in H9c2 cells and to determine the potential mechanism. In part 2, H9c2 cell viability was evaluated. ROS levels, mitochondrial morphology, and mitochondrial membrane potential of H9c2 cells were measured. ATP levels were evaluated using an assay kit; mitochondrial DNA (mtDNA), the expressions of NRF-1 and TFAM, and mitochondrial biogenesis factors were determined.ResultsNBP treatment significantly reduced the infarct ratio, as observed by TTC staining, decreased serum myocardial enzymes in MI, and restored heart mitochondrial enzymes (isocitrate dehydrogenase (ICDH), succinate dehydrogenase (SDH), malate dehydrogenase (MDH), and a-ketoglutarate dehydrogenase (a-KGDH) activities after MI. Moreover, in in vitro studies, NBP significantly increased the viability of H9c2 cells in a dose-dependent manner, reduced cell apoptosis, protected mitochondrial functions, elevated the cellular ATP levels, and promoted H2O2-induced mitochondrial biogenesis in H9c2 cardiomyoblasts.ConclusionCollectively, the results from both the in vivo and in vitro experiments suggested that NBP exerted a cardioprotective effect on cardiac ischemic injury via the regulation of mitochondrial function and biogenesis.

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

“…Mitochondrial mass, autophagy, and MB also increased in enalapril-treated rats [89]. The increased protein levels of NRF1 and TFAM, which are mitochondrial biogenesis factors, caused the restoration of mtDNA loss by oxidants [83]. Taken together, the increased MB may be a therapeutic strategy for heart injury.…”

“…The increased MB in cardiac aging is considered to be a compensatory maladaptive response to the damaged energy metabolism, which is also stimulated by age-related mtROS. Decreased MB is a vital mechanism responsible for myocardial injury and HF [83,84]. MB alleviates mitochondrial dysfunction induced by oxidative stress and thus is considered to be a novel repair mechanism in aged heart.…”

Dl‐3‐N‐butylphthalide promotes angiogenesis and upregulates sonic hedgehog expression after cerebral ischemia in rats

“…The beneficial effect of NBP is attributed to its anti-inflammatory, anti-apoptotic, antioxidant, pro-mitochondrial function, and pro-neurogenesis properties, etc. 9,[11][12][13] Previous studies found that NBP could protect the brain microvascular endothelial cells against oxygen-glucose deprivation (OGD) through increasing HIF-1α and Bcl-2 expression. NBP could also promote angiogenesis through the increased expression of angiogenic growth factors.…”

Anthocyanidin attenuates myocardial ischemia induced injury via inhibition of ROS‐JNK‐Bcl‐2 pathway: New mechanism of anthocyanidin action

“…Oxidative stress is a well‐known mechanism of MI‐induced injury. Thus, H 2 O 2 is used as oxidative stress model of MI (Tian et al, ). In the present study, in vitro mimic of myocardial ischemic‐induced oxidative stress was carried out by exposing the cultured cardiomyocytes, pretreated with different concentrations of anthocyanidin, to H 2 O 2 .…”

“…Thus, ROS together with activated JNK and inactive Bcl-2 cause severe damage to the cells, resulting in ischemia injury (Donovan, Becker, Konishi, & Bonni, 2002). Several studies have reported the involvement of ROS-JNK and Bcl-2 signaling in disease pathologies (Tian, He, Yang, & Liu, 2017;Zhu et al, 2018), where inhibition of this pathway had positive effects on disease attenuation (Lee, Lee, Ko, Hong, & Lee, 2010). ROS-induced oxidative injury often involves the participation of JNK and other cell death signaling pathways (Chen et al, 2016;Fan et al, 2017).…”