Inhibition of Calcineurin and Sarcolemmal Ca ²⁺ Influx Protects Cardiac Morphology and Ventricular Function in K _v 4.2N Transgenic Mice

Abstract

Background-Cardiac-targeted expression of truncated K v 4.2 subunit (K v 4.2N) reduces transient outward current (I to ) density, prolongs action potentials (APs), and enhances contractility in 3-to 4-week-old transgenic mice. By 13 to 15 weeks of age, these mice develop severely impaired cardiac function and signs of heart failure. In this study, we examined whether augmented contractility in K v 4.2N mice results from elevations in intracellular calcium ([Ca 2ϩ ] i ) secondary to AP prolongation and investigated the putative roles of calcineurin activation in heart disease development of K v 4.2N mice. Methods and Results-At 3 to 4 weeks of age, L-type Ca 2ϩ influx and peak [Ca 2ϩ ] i were significantly elevated in K v 4.2N myocytes compared with control because of AP prolongation. Cardiac calcineurin activity was also significantly elevated in K v 4.2N mice by 5 weeks of age relative to controls and increased progressively as heart disease developed. This was associated with activation of protein kinase C (PKC)-␣ and PKC-but not PKC-⑀, as well as increases in ␤-myosin heavy chain (␤-MHC) and reductions in sarcoplasmic/endoplasmic reticulum Ca 2ϩ -ATPase (SERCA)-2a expression. Treatment with either cyclosporin A or verapamil prevented increases in heart weight to body weight ratios, interstitial fibrosis, impaired contractility, PKC activation, and changes in the expression patterns of ␤-MHC and SERCA2a.Conclusions-Our results demonstrate that AP prolongation caused by I to reduction results in enhanced Ca 2ϩ cycling and hypercontractility in mice and suggests that elevations in [Ca 2ϩ ] i via I Ca,L and activation of calcineurin play a central role in disease development after I to reduction using the K v 4

LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

“…In rat ventricular myocytes, LY29 and LY30 inhibit the Kv1.5/2.1 potassium channels . Inhibition of potassium channels often results in changes in intracellular calcium levels (Tokuno et al, 1999;Doi et al, 2000;Tahara et al, 2001;Sah et al, 2002;Wang et al, 2006). Despite of the complexity of potassium channels and the coupling of intracellular potassium versus calcium concentration changes in cardiomyocytes, we have found that a general potassium channel blocker TEA inhibited CT from increasing [Ca 2+ ] i and inducing COX-2 expression.…”

“…Inhibition of potassium channels often lead to changes in intracellular calcium (Tokuno et al, 1999;Doi et al, 2000;Tahara et al, 2001;Sah et al, 2002;Wang et al, 2006) (Fig. 9A).…”

Chronic verapamil treatment remodelsICa,Lin mouse ventricle

“…Heart-to-body weight ratios were unchanged in Iso ϩ Ver and decreased in Ver-only pumps. Ver has been shown to prevent increases in heart-to-body weight ratio observed in hypertrophy models (34,42), and a decreased ventricular wet weight was demonstrated in chicken embryos treated with Ver (10). Despite similar, albeit unexpected, increases in HR by either Ver or Iso alone, Iso ϩ Ver antagonized the Ver-induced increase of Ca 2ϩ channels.…”

Calcineurin Increases Cardiac Transient Outward K+ Currents via Transcriptional Up-regulation of Kv4.2 Channel Subunits

“…Preventing excessive I to,f reductions may be of critical importance because changes in I to,f can lead to altered electrical and contractile properties of the myocardium, which may contribute to impaired pump function and arrhythmias (6, 48 -51). For example, we (48,52) and others (53) have shown previously that not only is I to,f an important determinant of action potential profile changes occurring in heart disease and regional differences in action potential profile, but I to,f is also a major regulator of the amplitude and kinetics of cardiac contraction in rodents and larger mammals by modulating Ca 2ϩ entry via L-type Ca 2ϩ channels. Thus, Cn activation not only induces hypertrophy, but also modulates the extent of the electrical and contractile changes induced as a result of I to,f reduction caused by hypertrophic stimuli.…”