Enhanced Activity by NKCC1 and Slc26a6 Mediates Acidic pH and Cl⁻ Movement after Cardioplegia-Induced Arrest of db/db Diabetic Heart

Abstract

Diabetic heart dysfunctions during cardiac surgeries have revealed several clinical problems associated with ion imbalance. However, the mechanism of ion imbalance mediated by cardioplegia and a diabetic heart is largely unclear. We hypothesized that ion transporters might be regulated differently in the diabetic heart and that the differentially regulated ion transporters may involve in ion imbalance of the diabetic heart after cardioplegic arrest. In this study, we modified the Langendorff-free cardioplegia method and identified the involved ion transporters after cardioplegia-induced arrest between wild type and db/db heart. Enhanced expression of Na+-K+-2Cl− cotransporter 1 (NKCC1) was observed in the db/db heart compared to the wild type heart. Enhanced NKCC1 activity was observed in the left ventricle of db/db mice compared to that of wild type after cardioplegia-induced arrest. The expression and activity of Slc26a6, a dominant Cl−/HCO3− exchanger in cardiac tissues, were enhanced in left ventricle strips of db/db mice compared to that of wild type. The Cl− transporting activity in left ventricle strips of db/db mice was dramatically increased as compared to that of wild type. Interestingly, expression of Slc26a6, as well as carbonic anhydrase IV as a supportive enzyme of Slc26a6, was increased in db/db cardiac strips compared to wild type cardiac strips. Thus, the enhanced Cl− transporting activity and expression by NKCC1 and Slc26a6 in db/db cardiac tissues after cardioplegia-induced arrest provide greater insight into enhanced acidosis and Cl− movement-mediated db/db heart dysfunction. Thus, we suggested that enhanced Cl− influx and HCO3− efflux through NKCC1 and Slc26a6 offer more acidic circumstances in the diabetic heart after cardioplegic arrest. These transporters should be considered as potential therapeutic targets to develop the next generation of cardioplegia solution for protection against ischemia-reperfusion injury in diabetic hearts.

Role of the Cation-chloride-cotransporters in Cardiovascular Disease

“…This method uses TI + as a surrogate of K + and a TI + sensitive fluorescent dye (FlixORTM) to visualize TI + uptake through channels in single cells. The Delpire group reported similar results between 86 Rb + and FluxOR [115]. Other techniques include the ammonium pulse technique which uses cardiac strips to measure acidification rate [116].…”

“…These findings further emphasizes NKCC1 methylation or histone modification as a potential biomarker in the diagnosis and management of hypertension. More recently, studies by Ji [86] and Andersen [87] et al found increased NKCC activity after cardioplegia induced arrest of diabetic hearts (n=5, P<0.001) and in post infarction heart failure (n=6-7) respectively. These findings indicate the potential role of NKCC in protection of the diabetic heart after cardioplegia infusions and remodelling after myocardial infarction.…”

Physiological and Pathological Functions of SLC26A6

“…Although the regulation mechanism of various ion transporters is complicated ( 19 ), studies have demonstrated that the expression of SLC26A6 and Cl − transporting activity are upregulated in the type 2 diabetic heart model, which reveals that effective SLC26A6 blockers may be efficient in regulating pH of type 2 diabetic hearts ( 122 ). Additionally, Cl − influx and efflux mediated by SLC26A6 may be beneficial to intracellular acidification in diabetic myocardium during cardioplegia-induced arrest ( 122 ). Evidences reveal that protein kinase C (PKC) can inhibit the transport activity of SLC26A6 ( 19 , 123 ).…”

A Cardioplegic Solution with an Understanding of a Cardiochannelopathy

“…In addition to cations such as H + and Ca 2+ , the HCO 3 − anion also plays an important role in heart tissues that express HCO 3 − transporters such as the Cl − /HCO 3 − exchanger SLC26A6, which is involved in HCO 3 − influx and efflux [5,64]. SLC26A6 is a Cl − /HCO 3 − exchanger and is mainly expressed in the kidneys and exocrine glands [65][66][67].…”