Modulation of cardiac fibrosis by Krüppel-like factor 6 through transcriptional control of thrombospondin 4 in cardiomyocytes

Sawaki, Daigo; Hou, Lianguo; Tomida, Shota; Sun, Junqing; Zhan, Hong; Aizawa, Kenichi; Son, Bo Kyung; Kariya, Taro; Takimoto, Eiki; Otsu, Kinya; Conway, Simon J.; Manabe, Ichiro; Komuro, Issei; Friedman, Scott L.; Nagai, Ryozo; Suzuki, Toru

doi:10.1093/cvr/cvv155

Cited by 41 publications

(26 citation statements)

References 46 publications

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“…The expression of TSP-4 in heart tissue was increased in various cardiac disease model animals [12,22,29,30]. Several studies reported that TSP-4 exerted a cardioprotective effect in cardiac diseases [12,30]. In the present study, TSP-4 prolonged APD with suppressing the activation of calcium and potassium channels.…”

Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

“…The expression of TSP-4 is known to increase in the heart tissue of patients with coronary artery disease and various heart disease model animals, such as pressure overload-induced hypertrophied mice, spontaneously-hypertensive rats and myocardial infarcted rats [12,13,23,29]. It has been reported that TSP-4 exerts a cardioprotective effect through the inhibition of interstitial fibrosis via regulation of cardiac fibroblasts [12,30]. TSP-4 gene knock-out inhibited the increase of stroke volume in transaortic-constriction (TAC) model mice.…”

Section: Introductionmentioning

confidence: 99%

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Thrombospondin-4 induces prolongation of action potential duration in rat isolated ventricular myocytes

Imoto

Aratani

Koyama

et al. 2020

The Journal of Veterinary Medical Science

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Expression of thrombospondin-4 (TSP-4), a matricellular protein, is increased in the heart tissue of various cardiac disease models. In dorsal root ganglion neurons, TSP-4 inhibits L-type Ca 2+ channel (LTCC) activity. Although TSP-4 might be related to the electrophysiological properties in heart, it remains to be clarified. The present study aimed to clarify the effects of TSP-4 on action potential (AP), LTCC current (ICaL) and voltage-dependent K + (Kv) channel current (IKv) in rat isolated ventricular myocytes by a patch clamp technique. Ventricular myocytes were isolated from the heart of adult male Wistar rats. The ventricular myocytes were treated with TSP-4 (5 nM) or its vehicle for 4 hr. Then, whole-cell patch clamp technique was performed to measure AP (current-clamp mode) and ICaL and IKv (voltage-clamp mode). The mRNA expression of Kv channels was examined by reverse transcription-polymerase chain reaction. TSP-4 had no effect on the resting membrane potential and peak amplitude of AP. On the other hand, TSP-4 significantly prolonged AP duration (APD) at 50% and 90% repolarization. TSP-4 significantly inhibited the peak amplitudes of ICaL and IKv. TSP-4 had no effect on mRNA expression of Kv channels (Kcna4, Kcna5, Kcnb1, Kcnd2 and Kcnd3). The present study for the first time demonstrated that TSP-4 prolongs APD in rat ventricular myocytes, which is possibly mediated through the suppression of Kv channel activity.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Thrombospondin-4 induces prolongation of action potential duration in rat isolated ventricular myocytes

Imoto

Aratani

Koyama

et al. 2020

The Journal of Veterinary Medical Science

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“…Rock1, two other key regulators of fibrosis. 26,27 This suggests that the molecular mechanism that drive cardiac fibrosis are sensitive to small perturbations in gene expression. Since therapeutical targeting of SOX9 would also moderately lower expression levels, we think this genetic model gives a good representation of what would happen when using an inhibitor of SOX9 in the clinic as a therapy for cardiac fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Tomo-Seq Identifies SOX9 as a Key Regulator of Cardiac Fibrosis During Ischemic Injury

et al. 2017

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“…This suggests that TSP-4 has a more direct role on the ECM remodeling process [59], but what this role is and the mechanism behind it are currently unclear. Upstream, TSP4 expression is regulated by the transcription factor krüppel-like factor 6 (KLF6) in order to regulate cardiac fibrosis [60] (Figure 2). …”

Section: Matrix Remodeling and Fibrosismentioning

confidence: 99%

Thrombospondins in the transition from myocardial infarction to heart failure

Kirk

Cingolani

2016

Journal of Molecular and Cellular Cardiology

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The heart’s reaction to ischemic injury from a myocardial infarction involves complicated cross-talk between the extra-cellular matrix (ECM) and many different cell types within the myocardium. The ECM functions not only as a scaffold where myocytes beat synchronously, but an active signaling environment that regulates the important post-MI responses. The thrombospondins are matricellular proteins that modulate cell - ECM interactions, functioning as “sensors” that mediate outside-in and inside-out signaling. Thrombospondins are highly expressed during embryonic stages, and although their levels decrease during adult life, can be re-expressed in high quantities in response to cardiac stress including myocardial infarction and heart failure. Like a swiss-army knife, the thrombospondins possess many tools: numerous binding domains that allow them to interact with other elements of the ECM, cell surface receptors, and signaling molecules. It is through these that the thrombospondins function. In the present review, we provide basic as well as clinical evidence linking the thrombospondin proteins with the post myocardial infarction response, including inflammation, fibrotic matrix remodeling, angiogenesis, as well as myocyte hypertrophy, apoptosis, and contractile dysfunction in heart failure. We will describe what is known regarding the intracellular signaling pathways that are involved with these responses, paving the road for future studies identifying these proteins as novel therapeutic targets for cardiac disease.

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Modulation of cardiac fibrosis by Krüppel-like factor 6 through transcriptional control of thrombospondin 4 in cardiomyocytes

Abstract: Our present studies on the cardiac function of KLF6 show a new mechanism whereby cardiomyocytes regulate cardiac fibrosis through transcriptional control of the extracellular matrix factor, TSP4, which, in turn, modulates activation of cardiac fibroblasts.

Cited by 41 publications

References 46 publications

Thrombospondin-4 induces prolongation of action potential duration in rat isolated ventricular myocytes

Thrombospondin-4 induces prolongation of action potential duration in rat isolated ventricular myocytes

Tomo-Seq Identifies SOX9 as a Key Regulator of Cardiac Fibrosis During Ischemic Injury

Thrombospondins in the transition from myocardial infarction to heart failure

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