Regulation of Coronary Arterial Large Conductance Ca²⁺-Activated K⁺ Channel Protein Expression and Function by n-3 Polyunsaturated Fatty Acids in Diabetic Rats

Abstract

Aim: The objective of this study was to examine the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs)on coronary arterial large conductance Ca²⁺-activated K⁺ (BK) channel function in coronary smooth muscle cells (SMCs) of streptozotocin-induced diabetic rats. Methods: The effects of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) on coronary BK channel open probabilities were determined using the patch clamp technique. The mRNA and protein expressions of BK channel subunits were measured using qRT-PCR and Western blots. The coronary artery tension and coronary SMC Ca²⁺ concentrations were measured using a myograph system and fluorescence Ca²⁺ indicator. Results: Compared to nondiabetic control rats, the BK channel function was impaired with a reduced response to EPA and DHA in freshly isolated SMCs of diabetic rats. Oral administration of n-3 PUFAs had no effects on protein expressions of BK channel subunits in nondiabetic rats, but significantly enhanced those of BK-β₁ in diabetic rats without altering BK-α protein levels. Moreover, coronary ring tension induced by iberiotoxin (a specific BK channel blocker) was increased and cytosolic Ca²⁺ concentrations in coronary SMCs were decreased in diabetic rats, but no changes were found in nondiabetic rats. Conclusions: n-3 PUFAs protect the coronary BK channel function and coronary vasoreactivity in diabetic rats as a result of not only increasing BK-β₁ protein expressions, but also decreasing coronary artery tension and coronary smooth muscle cytosolic Ca²⁺ concentrations.

BK Channel Dysfunction in Diabetic Coronary Artery: Role of the E3 Ubiquitin Ligases

“…In studies on streptozotocin (STZ)-induced type 1 diabetic models, similar changes of the BK channel were found as in type 2 diabetes mellitus (Lu et al, 2010;Zhang et al, 2010;Wang et al, 2012a,b;Tang et al, 2017). In STZ-induced diabetic rats, coronary BK-β1 subunit expression was also decreased and BKα subunit expression remained in the coronary artery (Wang et al, 2012a,b;Tang et al, 2017;Zhang et al, 2010).…”

“…In STZ-induced diabetic rats, coronary BK-β1 subunit expression was also decreased and BKα subunit expression remained in the coronary artery (Wang et al, 2012a,b;Tang et al, 2017;Zhang et al, 2010). Both open probability and current density were decreased in diabetic CASMCs, with coronary constriction to BK inhibitor iberiotoxin being markedly impaired (Wang et al, 2012a;Tang et al, 2017). The BK currents were decreased and the DHS-1-induced BK activation was impaired in CASMCs of STZ-induced diabetic rat (Zhang et al, 2010).…”

“…The BK currents were decreased and the DHS-1-induced BK activation was impaired in CASMCs of STZ-induced diabetic rat (Zhang et al, 2010). Most studies reported that the BK-β1 subunit protein expression was decreased without a change of the BK-α subunit (Zhang et al, 2010;Wang et al, 2012a,b;Tang et al, 2017). One study (Lu et al, 2010) showed that the BK channel expression was unchanged in diabetic rats, although the function of the BK channel is damaged.…”

Atorvastatin Calcium Inhibits PDGF-ββ-Induced Proliferation and Migration of VSMCs Through the G0/G1 Cell Cycle Arrest and Suppression of Activated PDGFRβ-PI3K-Akt Signaling Cascade

“…Previous studies showed that MMPs, specifically MMP-2 and MMP-9, were activated rapidly following vascular injury [36-38] and played an important role in disrupting the ECM in VSMCs [37, 39]. Degradation of the ECM promoted VSMC migration from the media of arterial walls to the intimal space, where VSMCs secreted more ECM products, progressively resulting in restenosis and neointima formation [40, 41].…”

Potassium channels in vascular smooth muscle: a pathophysiological and pharmacological perspective

“…The reduction in BK Ca ‐β1 expression in renal arterioles of type I diabetic patients and in cerebral artery of type II diabetic rats has been shown to result in an increase in the myogenic tone. N‐3 polyunsaturated fatty acids protect the coronary BK Ca function and vasoreactivity in diabetic rats as a result of not only increasing BK Ca ‐β1 expressions, but also decreasing artery tension and [Ca +2 ] i .…”