Mitochondria-Associated Endoplasmic Reticulum Membranes in Cardiovascular Diseases

Gao, Peng; Yan, Zhencheng; Zhu, Zhiming

doi:10.3389/fcell.2020.604240

Cited by 84 publications

(80 citation statements)

References 173 publications

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“…Many studies have shown that there is a physical and functional interaction between the ER and mitochondria. This interaction is involved in the regulation of atherosclerosis, myocardial hypertrophy, heart failure, and other cardiovascular diseases [ 20 ]. ER stress is a condition that is accelerated by the accumulation of unfolded/misfolded proteins after disturbances owing to a variety of physiological and pathological phenomena [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

The Downregulation of ADAM17 Exerts Protective Effects against Cardiac Fibrosis by Regulating Endoplasmic Reticulum Stress and Mitophagy

Guan

Zhang

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Background. A disintegrin and metalloproteinase 17 (ADAM17) is a transmembrane protein that is widely expressed in various tissues; it mediates the shedding of many membrane-bound molecules, involving cell-cell and cell-matrix interactions. We investigated the role of ADAM17 within mouse cardiac fibroblasts (mCFs) in heart fibrosis. Methods. mCFs were isolated from the hearts of neonatal mice. Effects of ADAM17 on the differentiation of mCFs towards myofibroblasts and their fibrotic behaviors following induction with TGF-β1 were examined. The expression levels of fibrotic proteins, such as collagen I and α-SMA, were assessed by qRT-PCR analysis and western blotting. Cell proliferation and migration were measured using the CCK-8 and wound healing assay. To identify the target gene for ADAM17, the protein levels of the components of endoplasmic reticulum (ER) stress and the PINK1/Parkin pathway were assessed following ADAM17 silencing. The effects of ADAM17 silencing or treatment with thapsigargin, a key stimulator of acute ER stress, on mCFs proliferation, migration, and collagen secretion were also examined. In vivo, we used a mouse model of cardiac fibrosis established by left anterior descending artery ligation; the mice were administered oral gavage with a selective ADAM17 inhibitor (TMI-005) for 4 weeks after the operation. Results. We found that the ADAM17 expression levels were higher in fibrosis heart tissues and TGF-β1-treated mCFs. The ADAM17-specific siRNAs decreased TGF-β1-induced increase in the collagen secretion, proliferation, and migration of mCFs. Knockdown of ADAM17 reduces the activation of mCFs by inhibiting the ATF6 branch of ER stress and further activating mitophagy. Moreover, decreased ADAM17 expression also ameliorated cardiac fibrosis and improved heart function. Conclusions. This study highlights that mCF ADAM17 expression plays a key role in cardiac fibrosis by regulating ER stress and mitophagy, thereby limiting fibrosis and improving heart function. Therefore, ADAM17 downregulation, within the physiological range, could exert protective effects against cardiac fibrosis.

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Section: Introductionmentioning

confidence: 99%

The Downregulation of ADAM17 Exerts Protective Effects against Cardiac Fibrosis by Regulating Endoplasmic Reticulum Stress and Mitophagy

Guan

Zhang

Wang

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…In addition, our results showed increased levels of the MAMs 75 kDa glucose-regulated protein (GRP75), sigma-1 receptor (SIG-1R) and mitofusin-2 (MFN2) proteins in PCCA iPSC-CMs in comparison with WT iPSC-CMs ( Figure 3 c). The structural and functional interactions between the ER and mitochondria are essential for normal cardiac function and alterations in the amount, structure or function of MAMs have been related to cardiovascular diseases [ 28 ]. Elevated expression of the ER stress markers GRP78, eIF2α and XBP1, and increased activation of the UPR, has been observed in patients with inherited dilated cardiomyopathy [ 29 ].…”

Section: Resultsmentioning

confidence: 99%

Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

Alonso-Barroso

Pérez

Desviat

et al. 2021

IJMS

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Propionic acidemia (PA), one of the most frequent life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes encoding both subunits of the mitochondrial propionyl-CoA carboxylase (PCC) enzyme. Cardiac alterations (hypertrophy, dilated cardiomyopathy, long QT) are one of the major causes of mortality in patients surviving the neonatal period. To overcome limitations of current cellular models of PA, we generated induced pluripotent stem cells (iPSCs) from a PA patient with defects in the PCCA gene, and successfully differentiated them into cardiomyocytes. PCCA iPSC-derived cardiomyocytes exhibited reduced oxygen consumption, an accumulation of residual bodies and lipid droplets, and increased ribosomal biogenesis. Furthermore, we found increased protein levels of HERP, GRP78, GRP75, SIG-1R and MFN2, suggesting endoplasmic reticulum stress and calcium perturbations in these cells. We also analyzed a series of heart-enriched miRNAs previously found deregulated in the heart tissue of a PA murine model and confirmed their altered expression. Our novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.

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“…The connection between ER and mitochondria is mediated by MAM, the mitochondrial-associated ER membrane [ 181 ]. MAM allows the exchange of several compounds, such as Ca 2+ , essential for controlling mitochondrial [ 193 ] and cell functions [ 189 ], as well as adaptation to pathophysiological conditions which require an enhanced metabolism [ 182 ]. Furthermore, this energy demand is enhanced in ER stress situation to control the composition and functions of MAM [ 181 ].…”

Section: Mechanisms Involved In Vascular Alterations Associated Wimentioning

confidence: 99%

“…Furthermore, this energy demand is enhanced in ER stress situation to control the composition and functions of MAM [ 181 ]. The accumulation of Ca 2+ within mitochondria as consequence of this exchange promotes an enhancement of ROS production and apoptosis [ 193 ]. In obese mice fed an HFD or high sucrose diet, where ER stress was induced by tunicamycin, MAM integrity was altered, impairing the interaction between the two organelles.…”

Section: Mechanisms Involved In Vascular Alterations Associated Wimentioning

confidence: 99%

“…In addition, other studies have found in aorta from mice fed an HFD, both altered MAM and mitochondria, as well as ER morphology in endothelial cells, which were associated with increased ROS production, overexpression of ER stress markers and endothelial dysfunction [ 182 ]. The traffic of Ca 2+ through MAMs is mediated by multiple proteins, including those of BCL family, which promote an increase of this traffic from ER to mitochondria as an adaptive response to the increase of the bioenergetics processes [ 193 ].…”

Section: Mechanisms Involved In Vascular Alterations Associated Wimentioning

confidence: 99%

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Oxidative Stress and Vascular Damage in the Context of Obesity: The Hidden Guest

et al. 2021

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The vascular system plays a central role in the transport of cells, oxygen and nutrients between different regions of the body, depending on the needs, as well as of metabolic waste products for their elimination. While the structure of different components of the vascular system varies, these structures, especially those of main arteries and arterioles, can be affected by the presence of different cardiovascular risk factors, including obesity. This vascular remodeling is mainly characterized by a thickening of the media layer as a consequence of changes in smooth muscle cells or excessive fibrosis accumulation. These vascular changes associated with obesity can trigger functional alterations, with endothelial dysfunction and vascular stiffness being especially common features of obese vessels. These changes can also lead to impaired tissue perfusion that may affect multiple tissues and organs. In this review, we focus on the role played by perivascular adipose tissue, the activation of the renin-angiotensin-aldosterone system and endoplasmic reticulum stress in the vascular dysfunction associated with obesity. In addition, the participation of oxidative stress in this vascular damage, which can be produced in the perivascular adipose tissue as well as in other components of the vascular wall, is updated.

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Mitochondria-Associated Endoplasmic Reticulum Membranes in Cardiovascular Diseases

Cited by 84 publications

References 173 publications

The Downregulation of ADAM17 Exerts Protective Effects against Cardiac Fibrosis by Regulating Endoplasmic Reticulum Stress and Mitophagy

The Downregulation of ADAM17 Exerts Protective Effects against Cardiac Fibrosis by Regulating Endoplasmic Reticulum Stress and Mitophagy

Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia

Oxidative Stress and Vascular Damage in the Context of Obesity: The Hidden Guest

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