Cardiac Cx43 and ECM Responses to Altered Thyroid Status Are Blunted in Spontaneously Hypertensive versus Normotensive Rats.

Matus Sykora,Tamara Egan Benova,Miroslav Barancik,Barbara Szeiffova Bacova,Narcis Tribulova,Stanislav Pavelka,Jan Slezak,Hana Rauchova,Lin Hai Kurahara,Peter Weismann,Tomas Soukup,Jitka Zurmanova

doi:10.3390/ijms20153758

Abstract

Heart function and its susceptibility to arrhythmias are modulated by thyroid hormones (THs) but the responsiveness of hypertensive individuals to thyroid dysfunction is elusive. We aimed to explore the effect of altered thyroid status on crucial factors affecting synchronized heart function, i.e., connexin-43 (Cx43) and extracellular matrix proteins (ECM), in spontaneously hypertensive rats (SHRs) compared to normotensive Wistar Kyoto rats (WKRs). Basal levels of circulating THs were similar in both strains. Hyperthyroid state (HT) was induced by injection of T3 (0.15 mg/kg b.w. for eight weeks) and hypothyroid state (HY) by the administration of methimazol (0.05% for eight weeks). The possible benefit of omega-3 polyunsaturated fatty acids (Omacor, 200 mg/kg for eight weeks) intake was examined as well. Reduced levels of Cx43 in SHRs were unaffected by alterations in THs, unlike WKRs, in which levels of Cx43 and its phosphorylated form at serine368 were decreased in the HT state and increased in the HY state. This specific Cx43 phosphorylation, attributed to enhanced protein kinase C-epsilon signaling, was also increased in HY SHRs. Altered thyroid status did not show significant differences in markers of ECM or collagen deposition in SHRs. WKRs exhibited a decrease in levels of profibrotic transforming growth factor β1 and SMAD2/3 in HT and an increase in HY, along with enhanced interstitial collagen. Short-term intake of omega-3 polyunsaturated fatty acids did not affect any targeted proteins significantly. Key findings suggest that myocardial Cx43 and ECM responses to altered thyroid status are blunted in SHRs compared to WKRs. However, enhanced phosphorylation of Cx43 at serine368 in hypothyroid SHRs might be associated with preservation of intercellular coupling and alleviation of the propensity of the heart to malignant arrhythmias.

Highlights

Heart function is profoundly regulated by thyroid hormones (THs)
In the context of the susceptibility of the heart to arrhythmias, we focused on exploring myocardial Cx43 and proteins involved in extracellular matrix proteins (ECM) turnover, such as matrix metalloproteinase-2 (MMP-2), transforming growth factor β1 (TGF-β1), and TGF transcription factor (SMAD2/3) in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKRs) in conditions of TH excess and deficiency
There were no differences in basal TH levels between Wistar Kyoto rats (WKRs) and SHRs

Summary

Introduction

Heart function is profoundly regulated by thyroid hormones (THs). Changes in circulating THs influence the basal activity of cardiomyocytes whereby the excess or deficiency of THs, resulting from thyroid dysfunction, is harmful to the heart [1,6,7,8]. In animal models [13], the hyperthyroid state increased and hypothyroid state decreased the propensity of the heart to ventricular fibrillation (VF). Hyperthyroid rats were more prone to developing AF [14]. The propensity to these arrhythmias was related to the myocardial protein level of connexin-43 (Cx43), which is downregulated because of excess THs and upregulated in TH deficiency [14,15,16,17]. Defects in protein abundance and distribution of Cx43 have been known to impair Cx43 channel-mediated intercellular electrical coupling, which is crucial in arrhythmogenesis [18,19]

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