Loss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling

Peng, Jianye; Liu, Yu; Xiong, Xiaoju; Huang, Congxin; Yang, Minghui; Wang, Zhiqiang; Tang, Yuqi; Ye, Jing; Kong, Bin; Liu, Wanli; Wang, Teng; Huang, He

doi:10.1038/s41598-017-05379-w

Cited by 33 publications

(51 citation statements)

References 66 publications

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“…In addition, alterations in Ca 2+ handling proteins in WT‐Aldo mice were significantly worsened in KO‐Aldo mice. A recent study indicated that MD1‐KO can interfere with the expression of Ca 2+ handling proteins in pressure‐induced HF mice . Therefore, there is strong and growing evidence that MD1 deletion worsens the dysregulation of calcium handling and increases the vulnerability of aldosterone‐induced HFpEF mice to AF.…”

Section: Discussionmentioning

confidence: 99%

“…The MD1‐RP105 complex can directly interact with the MD2‐TLR4 complex by lateral binding, acting as a negative physiological regulator of the TLR4 signalling pathway . Our previous study showed that MD1 is widely expressed in the heart, and MD1 deletion leads to a more pronounced activation of the TLR4/CaMKII signalling pathway, which may further significantly influence the expression levels of Ca 2+ handling proteins, increasing the vulnerability of HF mice to ventricular arrhythmia . Therefore, we hypothesized that MD1 deletion can alter calcium homoeostasis in atrial myocytes and increase susceptibility to AF in HFpEF by enhancing the activation of TLR4/CaMKII signalling.…”

Section: Introductionmentioning

confidence: 99%

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Loss of myeloid differentiation protein 1 promotes atrial fibrillation in heart failure with preserved ejection fraction

et al. 2020

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Aims Myeloid differentiation protein 1 (MD1) is expressed in the mammalian heart and exerts an anti-arrhythmic effect. Atrial fibrillation (AF) is closely related to heart failure with preserved ejection fraction (HFpEF). The potential impact of MD1 on AF vulnerability in an HFpEF model is not clear. Methods and results MD1 knock-out and wild-type (WT) mice were subjected to uninephrectomy and continuous saline or D-aldosterone infusion and given 1% sodium chloride drinking water for 4 weeks. Echocardiographic and haemodynamic measurements, electrophysiological studies, Masson staining, and molecular analysis were performed. Aldosterone-infused WT mice develop HFpEF with left ventricular hypertrophy, moderate hypertension, pulmonary congestion, and diastolic dysfunction. Aldosterone infusion increased the vulnerability of WT mice to AF, as shown by a prolonged interatrial conduction time, shortened effective refractory period, and higher incidence of AF. In addition, aldosterone infusion increased myocardial fibrosis and inflammation, decreased sarcoplasmic reticulum Ca 2+ -ATPase 2a protein expression and the phosphorylation of phospholamban at Thr17, and increased sodium/calcium exchanger 1 protein expression and the phosphorylation of ryanodine receptor 2 in WT mice. All of the above adverse effects of aldosterone infusion were further exacerbated in MD1 knock-out mice compare with WT mice. Mechanistically, MD1 deletion increased the activation of the toll-like receptor 4/calmodulindependent protein kinase II signalling pathway in in vivo and in vitro experiments. Conclusions MD1 deficiency increases the vulnerability of HFpEF mice to AF. This is mainly caused by aggravated maladaptive left atrial fibrosis and inflammation and worsened dysregulation of calcium handling, which is induced by the enhanced activation of the toll-like receptor 4/calmodulin-dependent protein kinase II signalling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of myeloid differentiation protein 1 promotes atrial fibrillation in heart failure with preserved ejection fraction

et al. 2020

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“…Our previous studies found that MD1 expression was downregulated in heart failure patients [6,7], and loss of MD1 could worsen structural and electrical remodeling under pressure overload and ischemia/reperfusion injury conditions via increased the activation of the TLR4 signaling pathway [6,8]. Interestingly, we also found that MD1 deletion had no significant effect on the cardiac structure in wild-type (WT) mice under physiological conditions [6][7][8][9][10][11]. Moreover, downregulated MD1 does not activate the TLR4 signaling pathway in both in vitro and in vivo experiments [7,9].…”

Section: Introductionmentioning

confidence: 96%

“…The MD1-RP105 complex can directly interact with the myeloid differentiation protein 2 (MD2)-Toll-like receptor 4 (TLR4) complex by a lateral binding, acting as a negative physiological regulator of the TLR4 signaling pathway [5]. Our previous studies found that MD1 expression was downregulated in heart failure patients [6,7], and loss of MD1 could worsen structural and electrical remodeling under pressure overload and ischemia/reperfusion injury conditions via increased the activation of the TLR4 signaling pathway [6,8]. Interestingly, we also found that MD1 deletion had no significant effect on the cardiac structure in wild-type (WT) mice under physiological conditions [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

The effect of MD1 on potassium and L-type calcium current of cardiomyocytes from high-fat diet mice

Shuai

Kong

et al. 2020

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Myeloid differentiation protein 1 (MD1) is exerted an anti-arrhythmic effect in obese mice. Therefore, we sought to clarify whether MD1 can alter the electrophysiological remodeling of cardiac myocytes from obese mice by regulating voltage-gated potassium current and calcium current. MD1 knockout (KO) and wild type (WT) mice were given a high-fat diet (HFD) for 20 weeks, starting at the age of 6 weeks. The potential electrophysiological mechanisms were estimated by whole-cell patch-clamp and molecular analysis. After 20-week HFD feeding, action potential duration (APD) from left ventricular myocytes of MD1-KO mice revealed APD 20 , APD 50 , and APD 90 were profoundly enlarged. Furthermore, HFD mice showed a decrease in the fast transient outward potassium currents (I to,f), slowly inactivating potassium current (I K, slow), and inward rectifier potassium current (I K1). Besides, HFD-fed mice showed that the current density of I CaL was significantly lower, and the haft inactivation voltage was markedly shifted right. These HFD induced above adverse effects were further exacerbated in KO mice. The mRNA expression of potassium ion channels (Kv4.2, Kv4.3, Kv2.1, Kv1.5, and Kir2.1) and calcium ion channel (Cav1.2) was markedly decreased in MD1-KO HFD-fed mice. MD1 deletion led to down-regulated potassium currents and slowed inactivation of L-type calcium channel in an obese mice model.

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“…In this manner, they may be implicated in neuronal injury in response to I/R or oxygen-glucose deprivation/reoxygenation (OGD/R) insult with respect to inflammation, apoptosis and ROS (7,8). RP105 is a member of the TLR family and acts as an endogenous inhibitor of TLR4, regulating acute/chronic myocardial ischemia and pressure overload-induced cardiac remodeling (9)(10)(11). Although the benefits have been well established for RP105 with regard to dependence on TLR4-limited patterns, data since has shown the effects of RP105 in TLR4-independent approaches (10).…”

Section: Introductionmentioning

confidence: 99%

RP105 protects PC12 cells from oxygen‑glucose deprivation/reoxygenation injury via activation of the PI3K/AKT signaling pathway

et al. 2018

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Radioprotective 105 kDa protein (RP105) has been reported to produce favorable outcomes in various cardiovascular disorders via a toll‑like receptor 4‑dependent or ‑independent manner. However, whether RP105 exerts neuroprotective effects against oxygen‑glucose deprivation (OGD)/reoxygenation (OGD/R) injury remains to be elucidated. In the present study, the PC12 neuronal cell line was exposed to 4 h of OGD followed by 24 h of reoxygenation. Adenoviral vectors encoding RP105 were utilized to upregulate the level of RP105 in PC12 cells prior to OGD/R induction. The results demonstrated that OGD/R reduced the expression of RP105 at the mRNA and protein levels. The overexpression of RP105 significantly reversed OGD/R‑induced neuronal injuries, as demonstrated by the reduced release of lactate dehydrogenate and enhanced cellular viability, in addition to decreased inflammation, apoptosis and reactive oxygen species. The mechanistic evaluations indicated that the neuroprotective functions of RP105 were, in part, a result of activation of the phosphatidylinositol 3‑kinase (PI3K)/protein kinase B (AKT) pathway. In addition, elimination of the PI3K/AKT axis via the use of a pharmacological inhibitor inhibited the OGD/R‑inhibitory effects induced by the overexpression of RP105. Taken together, RP105 protected PC12 cells from OGD/R injury through promotion of the PI3K/AKT pathway; therefore, the RP105‑PI3K‑AKT axis may provide a novel therapeutic target for the prevention of cerebral ischemia/reperfusion injury.

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Loss of MD1 exacerbates pressure overload-induced left ventricular structural and electrical remodelling

Cited by 33 publications

References 66 publications

Loss of myeloid differentiation protein 1 promotes atrial fibrillation in heart failure with preserved ejection fraction

Loss of myeloid differentiation protein 1 promotes atrial fibrillation in heart failure with preserved ejection fraction

The effect of MD1 on potassium and L-type calcium current of cardiomyocytes from high-fat diet mice

RP105 protects PC12 cells from oxygen‑glucose deprivation/reoxygenation injury via activation of the PI3K/AKT signaling pathway

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