apelin-13-peptide and Cardiotoxicity

Cyclophosphamide is a chemotherapeutic drug that is widely used in the clinic and can cause multi-organ toxicity. Apelin-13 is an endogenous adipocytokine with antioxidant properties. Therefore, this study investigated the possibility of apelin-13 being a potential therapeutic agent on cardiac toxicity and nephrotoxicity caused by cyclophosphamide. In this study, a total of four groups were formed with eight rats in each group. Group I: the control group was administered only saline (i.p.). Group II: cyclophosphamide, a single dose of 200 mg/kg (i.p.) on day 7. Group III: apelin-13 (15 μg/kg), for 7 days (i.p.). Group IV: administered apelin-13 (15 μg/kg) (i.p.) for 7 days and a single dose of cyclophosphamide (200 mg/kg) (i.p.) on day 7, the rats were sacrificed on day 8. Lactate dehydrogenase, cardiac troponin I (cTnI), creatine kinase MB (CK-MB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), malondialdehyde, creatinine, and blood urea nitrogen were found to be high in the cyclophosphamide group; however, these values were reduced with apelin-13 administration. Antioxidant enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and reduced glutathione (GSH) decreased in the cyclophosphamide group, and apelin-13 increased these enzyme activities. In addition, histopathological examinations also supported the results obtained. The findings of this study showed that apelin-13 has a protective effect against cardiorenal toxicity caused by cyclophosphamide.

Topics: Animals; Antioxidants; Cardiotoxicity; Cyclophosphamide; Intercellular Signaling Peptides and Proteins; Oxidative Stress; Rats; Rats, Wistar

Cardiotoxicity can be induced by the commonly used amide local anesthetic, bupivacaine. Bupivacaine can inhibit protein kinase B (AKT) phosphorylation and activated adenosine monophosphate-activated protein kinase alpha (AMPKα). It can decouple mitochondrial oxidative phosphorylation and enhance reactive oxygen species (ROS) production. Apelin enhances the phosphatidylinositol 3-kinase (PI3K)/AKT and AMPK/acetyl-CoA carboxylase (ACC) pathways, promotes the complete fatty acid oxidation in the heart, and reduces the release of ROS. In this study, we examined whether exogenous (Pyr1) apelin-13 could reverse bupivacaine-induced cardiotoxicity.. We used the bupivacaine-induced inhibition model in adult male Sprague Dawley (SD) rats (n = 48) and H9c2 cardiomyocyte cell cultures to explore the role of apelin-13 in the reversal of bupivacaine cardiotoxicity, and its possible mechanism of action. AMPKα, ACC, carnitine palmitoyl transferase (CPT), PI3K, AKT, superoxide dismutase 1 (SOD1), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p47-phox) were quantified. Changes in mitochondrial ultrastructure were examined, and mitochondrial DNA, cell viability, ROS release, oxygen consumption rate (OCR) were determined.. Apelin-13 reduced bupivacaine-induced mitochondrial DNA lesions in SD rats (P < .001), while increasing the expression of AMPKα (P = .007) and PI3K (P = .002). Furthermore, apelin-13 blocked bupivacaine-induced depolarization of the mitochondrial membrane potential (P = .019) and the bupivacaine-induced increases in ROS (P = .001). Also, the AMPK pathway was activated by bupivacaine as well as apelin-13 (P = .002) in H9c2 cardiomyocytes. Additionally, the reduction in the PI3K expression by bupivacaine was mitigated by apelin-13 in H9c2 cardiomyocytes (P = .001). While the aforementioned changes induced by bupivacaine were not abated by apelin-13 after pretreatment with AMPK inhibitor compound C; the bupivacaine-induced changes were still mitigated by apelin-13, even when pretreated with PI3K inhibitor-LY294002.. Apelin-13 treatment reduced bupivacaine-induced oxidative stress, attenuated mitochondrial morphological changes and mitochondrial DNA damage, enhanced mitochondrial energy metabolism, and ultimately reversed bupivacaine-induced cardiotoxicity. Our results suggest a role for the AMPK in apelin-13 reversal of bupivacaine-induced cardiotoxicity.

Topics: AMP-Activated Protein Kinases; Animals; Bupivacaine; Cardiotoxicity; Cell Line; Disease Models, Animal; DNA Damage; Heart Diseases; Intercellular Signaling Peptides and Proteins; Male; Mitochondria, Heart; Myocytes, Cardiac; Oxidative Stress; Phosphatidylinositol 3-Kinase; Rats, Sprague-Dawley; Signal Transduction