Connexins and Nitric Oxide Inside and Outside Mitochondria: Significance for Cardiac Protection and Adaptation

Maria Shvedova; Yana Anfinogenova; Sergey V Popov; Dmitriy N Atochin

doi:10.3389/fphys.2018.00479

Connexins and Nitric Oxide Inside and Outside Mitochondria: Significance for Cardiac Protection and Adaptation

Front Physiol. 2018 May 16:9:479. doi: 10.3389/fphys.2018.00479. eCollection 2018.

Authors

Maria Shvedova¹, Yana Anfinogenova^{2

3}, Sergey V Popov², Dmitriy N Atochin^{1

3}

Affiliations

¹ Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States.
² Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia.
³ RASA Center, National Research Tomsk Polytechnic University, Tomsk, Russia.

Abstract

Irreversible myocardial damage happens in the presence of prolonged and severe ischemia. Several phenomena protect the heart against myocardial infarction and other adverse outcomes of ischemia and reperfusion (IR), namely: hibernation related to stunned myocardium, ischemic preconditioning (IPC), ischemic post-conditioning, and their pharmacological surrogates. Ischemic preconditioning consists in the induction of a brief IR to reduce damage of the tissue caused by prolonged and severe ischemia. Nitric oxide (NO) signaling plays an essential role in IPC. Nitric oxide-sensitive guanylate cyclase/cyclic guanosine-3',5'-monophosphate (cGMP)-dependent protein kinase type I-signaling pathway protects against the IR injury during myocardial infarction. Mitochondrial ATP-sensitive and Ca²⁺-activated K⁺ channels are involved in NO-mediated signaling in IPC. Independently of the cGMP-mediated induction of NO production, S-nitrosation represents a regulatory molecular mechanism similar to phosphorylation and is essential for IPC. Unlike conditioning phenomena, the mechanistic basis of myocardial stunning and hibernation remains poorly understood. In this review article, we hypothesize that the disruption of electrical syncytium of the myocardium may underly myocardial stunning and hibernation. Considering that the connexins are the building blocks of gap junctions which represent primary structural basis of electrical syncytium, we discuss data on the involvement of connexins into myocardial conditioning, stunning, and hibernation. We also show how NO-mediated signaling is involved in myocardial stunning and hibernation. Connexins represent an essential element of adaptation phenomena of the heart at the level of both the cardio- myocytes and the mitochondria. Nitric oxide targets mitochondrial connexins which may affect electrical syncytium continuum in the heart. Mitochondrial connexins may play an essential role in NO-dependent mechanisms of myocardial adaptation to ischemia.

Keywords: connexins; ischemia; mitohodria; nitric oxide synthase; pre-conditioning.

Publication types

Review