Microrna 143–145 Deficiency Impairs Vascular Function

Norata, Giuseppe Danilo; Pinna, Christian; Zappella, F.; Elia, Leonardo; Sala, A.; Condorelli, Gianluigi; Catapano, Alberico L.

doi:10.1177/039463201202500216

Cited by 29 publications

(25 citation statements)

References 15 publications

(35 reference statements)

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“…The findings of the study confirm that miR-145 is an important vasculoprotective miR. Actually, miR-143/145 deficiency impairs vascular function (31). Restoration of miR-145 expression can limit neointimal formation in response to vascular injury by promoting Klf4 downregulation (6).…”

Section: Discussionsupporting

confidence: 60%

Angiotensin II Downregulates MicroRNA-145 to Regulate Kruppel-like Factor 4 and Myocardin Expression in Human Coronary Arterial Smooth Muscle Cells under High Glucose Conditions

Shyu

Cheng²,

Wang³

2015

Mol Med

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MicroRNA (miR)-145 is the most abundant miR in vascular smooth muscle cells (VSMCs). However, the effect of hyperglycemia on the regulation of miR-145 is unknown. We hypothesized that the hyperglycemic condition activates a proinflammatory response that mediates the expression of miR-145 in VSMCs. We investigated whether miR-145 serves as a critical regulator to regulate the downstream proliferation factors (including Kruppel-like factor 4 [Klf4] and myocardin) in VSMCs under hyperglycemic conditions. Human coronary artery smooth muscle cells (HCASMCs) were cultured under high glucose conditions. Sustained high glucose at 25 mmol/L significantly decreased the expression of miR-145 in HCASMCs. High glucose significantly increased angiotensin II (Ang II) secretion from HCASMCs and Ang II suppressed miR-145 expression in HCASMCs. Ang II repression of miR145 expression resulted in increased Klf4 and decreased myocardin expression under conditions of high glucose. Overexpression of miR-145 significantly decreased Klf4 and increased myocardin expression and inhibited HCASMC proliferation and migration induced by a high glucose state. Balloon injury of the carotid artery in diabetic rats was performed to investigate miR-145, Klf and myocardin expression. The expression of miR-145 was maximally increased at 7 d after carotid injury and gradually declined thereafter. Overexpression of miR-145 and treatment with valsartan reversed Klf4 and myocardin protein expression induced by balloon injury and improved vascular injury. In conclusion, our study reveals that Ang II downregulates miR-145 to regulate Klf4 and myocardin expression in HCASMCs under high glucose conditions. Ang II plays a critical role in the regulation of miR-145 under hyperglycemic conditions.

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Section: Discussionsupporting

confidence: 60%

Angiotensin II Downregulates MicroRNA-145 to Regulate Kruppel-like Factor 4 and Myocardin Expression in Human Coronary Arterial Smooth Muscle Cells under High Glucose Conditions

Shyu

Cheng²,

Wang³

2015

Mol Med

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“…45 The miR-143/145 cluster has been observed to play a fundamental role governing SMC differentiation during physiological and pathological events. 8,10,[15][16][17][18] Beside its ability to regulate SMC homeostasis, it is still not well understood how the miR-143/145 cluster regulates EC functions. In this report, we demonstrate that the modulation of the angiogenic potential of ECs is also due to the direct transfer of miR-143/145 from SMCs.…”

Section: Discussionmentioning

confidence: 99%

“…Other groups, [15][16][17] as well as ours, 8,10,18 have described the role of these miRNAs in the regulation of vascular homeostasis. In particular, we have demonstrated a critical role of the miR-143/145 cluster in SMC differentiation and vascular pathogenesis.…”

mentioning

confidence: 82%

TGFβ Triggers miR-143/145 Transfer From Smooth Muscle Cells to Endothelial Cells, Thereby Modulating Vessel Stabilization

et al. 2015

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Rationale: The miR-143/145 cluster is highly expressed in smooth muscle cells (SMCs), where it regulates phenotypic switch and vascular homeostasis. Whether it plays a role in neighboring endothelial cells (ECs) is still unknown. Objective: To determine whether SMCs control EC functions through passage of miR-143 and miR-145. Methods and Results: We used cocultures of SMCs and ECs under different conditions, as well as intact vessels to assess the transfer of miR-143 and miR-145 from one cell type to another. Imaging of cocultured cells transduced with fluorescent miRNAs suggested that miRNA transfer involves membrane protrusions known as tunneling nanotubes. Furthermore, we show that miRNA passage is modulated by the transforming growth factor (TGF) β pathway because both a specific transforming growth factor-β (TGFβ) inhibitor (SB431542) and an shRNA against TGFβRII suppressed the passage of miR-143/145 from SMCs to ECs. Moreover, miR-143 and miR-145 modulated angiogenesis by reducing the proliferation index of ECs and their capacity to form vessel-like structures when cultured on matrigel. We also identified hexokinase II ( HKII ) and integrin β 8 ( ITGβ8 )—2 genes essential for the angiogenic potential of ECs—as targets of miR-143 and miR-145, respectively. The inhibition of these genes modulated EC phenotype, similarly to miR-143 and miR-145 overexpression in ECs. These findings were confirmed by ex vivo and in vivo approaches, in which it was shown that TGFβ and vessel stress, respectively, triggered miR-143/145 transfer from SMCs to ECs. Conclusions: Our results demonstrate that miR-143 and miR-145 act as communication molecules between SMCs and ECs to modulate the angiogenic and vessel stabilization properties of ECs.

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“…MiRNAs are implicated in the pathogenesis of various cardiovascular diseases and have also been considered as potential targets for therapeutic intervention [2]. To date, several miRNAs have been described to finely regulate lipid metabolism and the progression and regression of atherosclerosis including miR-122, miR-33, miR-106, miR-758, miR-26, miR-370, miR-378/378*, let-7, miR-27, miR-103, miR-107, miR34a, miR-143 and miR-335 [3–20]. More recently, miRNAs were shown to exert their activities in cells different from those were they have been generated and also systemically.…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs and lipoproteins: A connection beyond atherosclerosis?

et al. 2013

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MicroRNAs (miRNAs) are involved in the pathogenesis of a number of cardiovascular diseases. In this review article, we have summarized the role of miRNAs in regulating lipid metabolism and how their therapeutical inhibition may lead to new approaches to treat cardiometabolic diseases, including atherosclerosis and metabolic syndrome. Specific miRNAs, such as miR-33a and -33b, represent one of the most interesting and attractive targets for metabolic-related disorders and anti-miR33 approaches are under intensive investigation. In addition to miR-33, other miRNAs, including miR-122, are also emerging as key players in lipid metabolism. More recently miRNAs were shown to exert their activities in a paracrine manner and also systemically. The latter is possible due to lipid-carriers, including lipoproteins, that transport and protect miRNAs from degradation. The emerging strong connection between miRNAs, lipoproteins and lipid metabolism indicates the existence of a reciprocal modulation that might go beyond atherosclerosis.

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Microrna 143–145 Deficiency Impairs Vascular Function

Cited by 29 publications

References 15 publications

Angiotensin II Downregulates MicroRNA-145 to Regulate Kruppel-like Factor 4 and Myocardin Expression in Human Coronary Arterial Smooth Muscle Cells under High Glucose Conditions

Angiotensin II Downregulates MicroRNA-145 to Regulate Kruppel-like Factor 4 and Myocardin Expression in Human Coronary Arterial Smooth Muscle Cells under High Glucose Conditions

TGFβ Triggers miR-143/145 Transfer From Smooth Muscle Cells to Endothelial Cells, Thereby Modulating Vessel Stabilization

MicroRNAs and lipoproteins: A connection beyond atherosclerosis?

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