NADPH Oxidase Hyperactivity Contributes to Cardiac Dysfunction and Apoptosis in Rats with Severe Experimental Pancreatitis through ROS-Mediated MAPK Signaling Pathway

Abstract

NADPH oxidase (Nox) is considered a major source of reactive oxygen species (ROS) in the heart in normal and pathological conditions. However, the role of Nox in severe acute pancreatitis- (SAP-) associated cardiac injury remains unclear. Therefore, we aim to investigate the contribution of Nox to SAP-associated cardiac injury and to explore the underlying molecular mechanisms. Apocynin, a Nox inhibitor, was given at 20 mg/kg for 30 min before SAP induction by a retrograde pancreatic duct injection of 5% sodium taurocholate. Histopathological staining, Nox activity and protein expression, oxidative stress markers, apoptosis and associated proteins, cardiac-related enzyme indexes, and cardiac function were assessed in the myocardium in SAP rats. The redox-sensitive MAPK signaling molecules were also examined by western blotting. SAP rats exhibited significant cardiac impairment along with increased Nox activity and protein expression, ROS production, cell apoptosis, and proapoptotic Bax and cleaved caspase-3 protein levels. Notably, Nox inhibition with apocynin prevented SAP-associated cardiac injury evidenced by a decreased histopathologic score, cardiac-related enzymes, and cardiac function through the reduction of ROS production and cell apoptosis. This protective role was further confirmed by a simulation experiment in vitro. Moreover, we found that SAP-induced activation in MAPK signaling molecules in cardiomyocytes was significantly attenuated by Nox inhibition. Our data provide the first evidence that Nox hyperactivation acts as the main source of ROS production in the myocardium, increases oxidative stress, and promotes cell apoptosis via activating the MAPK pathway, which ultimately results in cardiac injury in SAP.

Apocynin prevents reduced myocardial nerve growth factor, contributing to amelioration of myocardial apoptosis and failure

“…NADPH oxidase activity is increased in heart failure 22 . Apocynin is known to inhibit NADPH oxidase and oxidative stress 10,23 . In the present study, we found that apocynin improved LV function after MI.…”

Oxidative Stress, Kinase Activity and Inflammatory Implications in Right Ventricular Hypertrophy and Heart Failure under Hypobaric Hypoxia

“…Canonical MAPK signaling is mediated through three-kinase cascades beginning with an upstream MAPKKK (MEKK) and leading sequentially to MEK and to effector MAPKs, such as c-Jun N-terminal kinases (JNK), p38 and extracellular signal-regulated kinases (ERK) [ 22 ]. It is important to highligh that JNK, p38 and ERK are considered redox-sensitive kinases, and their activity is usually reported to regulate inflammation and apoptosis of cardiomyocytes [ 60 , 61 ].…”

Molecular insights of NADPH oxidases and its pathological consequences

“…Excessive ROS generation through NOX‐2 and NOX‐4 has been associated with apoptotic cell death of cardiac cells resulting in cardiac dysfunction and pathogenesis. It has been found that hyperactivation of NOX elevates ROS generation that further activates the MAPK pathway and promotes apoptosis in the myocardium that may cause cardiac injury in severe acute pancreatitis (SAP) 41 . Moreover, the deregulation of NOX‐2 contributes to angiotensin II‐induced cardiomyocyte hypertrophy, atrial fibrillation, and the development of interstitial fibrosis.…”