Cardiovascular Toxicology

Gong, Fangxiao; Jin, Jun; Li, Hengjie; Mao, Hui

doi: 10.1007/s12012-022-09766-2pmid: 35930219

As a widely used anti-tumor anthracycline, the accumulation of Doxorubicin (DOX) in body causes irreparable cardiomyocyte damage and therefore is limited in clinical application. Strategies to prevent from DOX-associated cardiotoxicity are urgent for patients who undergo DOX-based chemotherapy. Since oxidative stress injury being the major reason for myocardial toxicity of DOX, here we demonstrated that, Alpha-lipoic acid (ALA), which is a reductive agent, plays a cardioprotective role in attenuating DOX-induced cardiotoxicity by inhibiting pyruvate dehydrogenase kinase 4 (PDK4) expression. In vivo, the beneficial effect of ALA was evidenced by increased survival rate, mechanical contraction, and oxidative phosphorylation, while decreased reactive oxidative species (ROS) and apoptosis. In vitro, PDK4 overexpression remarkably increased DOX-induced apoptosis and ROS production in H9C2 cells. Notably, the protective effect of ALA was abrogated by PDK4 overexpression. We further used PDK4 knockout mice to identify the role of PDK4 in DOX-induced cardiotoxicity. Results elicited that PDK4 deficiency showed a consistent effect in protecting DOX cardiotoxicity as ALA treatment, which was evidenced by restored redox homeostasis and mitochondrial metabolism, finally inhibited myocardial injury. In conclusion, the cardioprotective role of ALA against DOX cardiotoxicity was dependent on PDK4-mediated regulation of oxidative stress and mitochondria metabolism.Graphical abstract[graphic not available: see fulltext]

Guo, Kai; Chen, Mantian; Li, Jinxiang

doi: 10.1007/s12012-022-09756-4pmid: 35727506

Programmed cell death protein 1 (PD-1) inhibitors open a new era of cancer immunotherapy, but they are associated with immune-related adverse events (irAEs) involving multiple endocrine organs of which thyroid dysfunction is the most common An uncommon condition of coronary artery spasm and ventricular tachycardia associated with thyrotoxicosis, induced by a PD-1 inhibitor, is discussed in this case. A 60-year-old male patient with a 1-week history of chest tightness and palpitation at rest was referred to us in July 2021. No obvious abnormalities were noted on physical examination and electrocardiography. He was being treated with a PD-1 inhibitor (camrelizumab, 200 mg) for lung metastasis of liver cancer; treatment stopped because he was found to have hyperthyroidism. Holter recorded intermittent STsegment arch back raised 0.5–14 mm upward lasting for 1–5 min, accompanied by ventricular tachycardia. He was treated with antivasospasm drugs (isosorbide mononitrate and diltiazem). Thyroid function was reexamined and revealed elevated FT3 and FT4 levels, decreased TSH levels, and negative thyroid-associated antibodies. After antivasospasm treatment and iodine taboo diet, his symptoms were relieved, and ST-segment elevation and ventricular tachycardia were disappeared. This case adds to our knowledge of the association between coronary artery spasms and thyrotoxicosis, which is an irAE induced by a PD-1 inhibitor. Patients treated with PD-1 inhibitors need regular follow-ups for cardiac complications, especially those with a history of heart disease.

Niu, Li-Gang; Sun, Na; Liu, Kai-Li; Su, Qing; Qi, Jie; Fu, Li-Yan; Xin, Guo-Rui; Kang, Yu-Ming

doi: 10.1007/s12012-022-09765-3pmid: 35986807

Hypertension caused by a high-salt (HS) diet is one of the major causes of cardiovascular diseases. Underlining pathology includes oxidative stress and inflammation in the hypothalamic paraventricular nucleus (PVN). This study investigates genistein’s (Gen) role in HS-induced hypertension and the underlying molecular mechanism. We placed male Wistar rats on HS (8% NaCl) or normal salt diet (0.3% NaCl). Then, we injected bilateral PVN in rats with Gen, vehicle, or nicotinamide (NAM) for 4 weeks. Tail cuff was used weekly to assess the systolic pressure, diastolic pressure, and mean arterial pressure (MAP). Cardiac hypertrophy was analyzed by heart weight/body weight ratio and wheat germ agglutinin staining. ELISA kits, Western blot, or dihydroethidium staining determined the levels of inflammatory cytokines and oxidative stress markers. Western blot measured protein levels of Sirt1, Ac-FOXO1, Nrf2, NQO-1, HO-1, and gp91phox. Our result showed that PVN infusion of Gen significantly reduced the increase of systolic pressure, diastolic pressure, and MAP induced by an HS diet. Additionally, there was a decrease in cardiac hypertrophy and the levels of inflammatory cytokines in PVN and plasma. Meanwhile, PVN infusion of Gen notably inhibited the levels of oxidized glutathione and superoxide dismutase and improved the glutathione level and total antioxidant capacities and superoxide dismutase activities. It also decreased the level of reactive oxygen species and gp91phox expression in PVN. Furthermore, Gen infusion markedly increases the Sirt1, Nrf2, HO-1, and NQO-1 levels and decreases the Ac-FOXO1 level. However, PVN infusion of NAM could significantly block these changes induced by Gen in HS diet rats. Our results demonstrated that PVN infusion of Gen could inhibit the progression of hypertension induced by an HS diet by activating the Sirt1/Nrf2 pathway.

Yang, Chuang; Jiang, Guopan; Xing, Yue

doi: 10.1007/s12012-022-09767-1pmid: 36125702

Acute myocardial infarction (AMI) leads to anoxia and ischemia of cardiomyocytes, followed by apoptosis. This study investigated the protective effect of ginsenoside Rg1 (Rg1) on myocardial ischemia injury in rats with AMI. Rats were randomly divided into five groups: group A (blank control group), group B (hypoxia/reoxygenation group), group C (hypoxia/reoxygenation + 10 mg/L Rg1), group D (hypoxia/reoxygenation + 20 mg/L Rg1) and group E (hypoxia/reoxygenation + 40 mg/L Rg1). The survival rate, apoptosis rate, expression of cyclin-dependent kinase 4 (CDK4), fibroblast growth factor 9 (FGF9), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), microvessel density and myocardial infarction area of rats in each group were compared. The expressions of CDK4 and FGF9, the contents of SOD and GSH-Px in groups C, D and E injected with Rg1 were significantly promoted compared to group B without Rg1 injection (P < 0.05). The survival rate of myocardial cells was significantly increased while the apoptosis rate was significantly decreased in group C, D, E compared to group B (P < 0.05). On the 3rd, 7th and 10th day following Rg1 treatment, the infarct area of E group was significantly decreased in three groups C, D, E, and the microvessel density of infarct area was significantly increased compared with group B (P < 0.05). So, Rg1 can improve the survival rate of myocardial cells, reduce the apoptosis rate and the area of myocardial infarction, and increase the microvessel density of infarct area, thus playing a protective role in ischemic myocardial cells of AMI rats.

Refaie, Marwa M. M.; Rifaai, Rehab Ahmed; Fawzy, Michael Atef; Shehata, Sayed

doi: 10.1007/s12012-022-09768-0pmid: 36242756

Cadmium (Cd) is a common environmental pollutant that leads to severe cardiotoxic hazards. Several studies were carried out to protect the myocardium against Cd-induced cardiotoxicity. Up till now, no researches evaluated the protective effect of dapagliflozin (DAP) against Cd induced cardiotoxicity. Thus, we aimed to explore the role of DAP in such model with deep studying of the involved mechanisms. 40 male Wistar albino rats were included in current study. Cd (5 mg/kg/day) was administered orally for 7 days to induce cardiotoxicity with or without co-administration of DAP in three different doses (2.5, 5, 10 mg/kg/day) orally for 7 days. Our data revealed that Cd could induce cardiotoxicity with significant increase in serum cardiac enzymes, heart weight, tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), nuclear factor kappa B (NFκB), toll like receptor2 (TLR2), interleukin 6 (IL6) and caspase3 immunoexpression with abnormal histopathological changes. In addition, Cd significantly decreased the level of heme oxygenase1 (HO1), nuclear factor erythroid 2-related factor 2 (Nrf2), signal transducer and activator of transcription (STAT3), reduced glutathione (GSH), glutathione peroxidase (GPx), and total antioxidant capacity (TAC). Co-administration of DAP could ameliorate Cd cardiotoxicity with significant improvement of the biochemical and histopathological changes. We found that DAP had protective properties against Cd induced cardiotoxicity and this may be due to its anti-oxidant, anti-inflammatory, anti-apoptotic properties and modulation of IL6/STAT3 and TLR2/TNFα-signaling pathways.