Functional Study of TREK-1 Potassium Channels During Rat Heart Development and Cardiac Ischemia Using RNAi Techniques

Abstract

To explore the physiological and pathological significance of the 2-pore domain potassium channel TWIK-related K(+) (TREK)-1 in rat heart, its expression and role during heart development and cardiac ischemia were investigated. In the former study, the ventricles of Sprague Dawley rats were collected from embryo day 19 to postnatal 18 months and examined for mRNA and protein expression of TREK-1. It was found that both increased during development, reached a maximum at postnatal day 28, and remained higher at postnatal day 3 through to postnatal 18 months. In the latter study, protein expression of TREK-1 was examined after initiation of acute heart ischemia by ligation of the left anterior descending coronary artery. TREK-1 expression was found to be increased in the endocardium but unchanged in the epicardium. In primary cultured rat neonatal ventricular myocytes subjected to hypoxia (oxygen-glucose deprivation), TREK-1 expression was increased. In cultured neonatal cardiomyocytes, silencing of the TREK-1 gene by lentivirus delivery of the short-hairpin RNAs, L-sh-492 and L-sh-605, was found to promote their viability and number. In addition, both short-hairpin RNA provided protection against hypoxia-induced injury to cardiomyocytes in vitro. These results suggest that TREK-1 plays an important role in neonatal rat heart development and downregulation of TREK-1 may provide protection against ischemic injury. It seems that TREK-1 is a potential drug target for treatment of acute heart ischemia.

TREK-1 protects the heart against ischemia-reperfusion-induced injury and from adverse remodeling after myocardial infarction

“…The most striking finding was that TREK-1 KO hearts were more susceptible to I/R-induced cardiac damage than the control counterpart. This is somewhat different from a previous finding showing that TREK-1 knockdown in neonatal rat cardiomyocytes is protective against ischemic damage in vitro [35]. Nevertheless, neonatal rat cardiomyocytes are not fully differentiated characterized by an hypometabolic status and are more tolerant to ischemia than the adult mouse hearts [2,23].…”

Identification and characterization of two zebrafish Twik related potassium channels, Kcnk2a and Kcnk2b

“…KCNK2 also acts as a cytoplasmic pH sensor whereby increasing intracellular acidity induces channel activation 8 , 9 . This particular property suggests a putative protective role for KCNK2 against ischemia and pain, in which disrupted metabolism promotes intracellular acidification 29 , 42 – 44 . Consequently, the increasing acidity triggers KCNK2 to open resulting in cell membrane hyperpolarisation, a protective phenomenon also produced by ATP sensitive potassium channels during cardiac and cerebral ischemia 45 , 46 .…”

The lectin LecA sensitizes the human stretch-activated channel TREK-1 but not Piezo1 and binds selectively to cardiac non-myocytes

“…From a pathophysiological point of view, sensitization of TREK-1 by LecA might be a starting point for novel therapeutic targeting of atrial fibrillation or heart failure -two pathologies where TREK-1 has been reported to be suppressed (Lugenbiel et al, 2017). Furthermore, TREK-1 inhibits proliferation of neuronal stem cells, astrocytes, osteoblasts, Chinese hamster ovary cells, and neonatal cardiomyocytes (Hughes et al, 2006;Xi et al, 2011;Wang et al, 2012;Yang et al, 2014;Zhang et al, 2016), but increases the proliferation of prostate cancer cell lines (Voloshyna et al, 2008). A compound that enhances TREK-1 opening might help controlling pathological tissue remodeling associated with non-myocyte proliferation in the heart.…”