Extracellular Matrix Secretion by Cardiac Fibroblasts: Role of microRNA-29b and microRNA-30c

Melanie Abonnenc; Adam A Nabeebaccus; Ursula Mayr; Javier Barallobre-Barreiro; Xuebin Dong; Friederike Cuello; Sumon Sur; Ignat Drozdov; Sarah Langley; Ruifang Lu; Konstantina Stathopoulou; Athanasios Didangelos; Xiaoke Yin; Wolfram H Zimmermann; Ajay M Shah; Anna Zampetaki; Manuel Mayr

doi:10.1161/CIRCRESAHA.113.302400

Extracellular Matrix Secretion by Cardiac Fibroblasts: Role of microRNA-29b and microRNA-30c

Melanie Abonnenc, Adam A Nabeebaccus, Ursula Mayr, Javier Barallobre-Barreiro, Xuebin Dong, Friederike Cuello, Sumon Sur, Ignat Drozdov, Sarah Langley, Ruifang Lu, Konstantina Stathopoulou, Athanasios Didangelos, Xiaoke Yin, Wolfram H Zimmermann, Ajay M Shah, Anna Zampetaki, Manuel Mayr

Research output: Contribution to journal › Article › peer-review

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Abstract

Rationale: MicroRNAs (miRNAs), in particular miR-29b and miR-30c, have been implicated as important regulators of cardiac fibrosis. Objective: To perform a proteomics comparison of miRNA effects on extracellular matrix (ECM) secretion by cardiac fibroblasts (CFs). Methods and Results: Mouse CFs were transfected with pre-/anti-miR of miR-29b and miR-30c and their conditioned medium was analysed by mass spectrometry. MiR-29b targeted a cadre of proteins involved in fibrosis, including multiple collagens, matrix metalloproteinases, and leukemia inhibitory factor (LIF), insulin-like growth factor-1 (IGF-1) and pentraxin-3, three predicted targets of miR-29b. MiR-29b even attenuated the CF response to TGFβ. In contrast, miR-30c had little effect on ECM production, but opposite effects with regards to LIF and IGF-1. Both miRNAs indirectly affected cardiac myocytes: Upon transfection with pre-miR-29b, the conditioned medium of CFs lost its ability to support adhesion of rat ventricular myocytes and led to a significant reduction of cardiac myocyte proteins (alpha-actinin, cardiac myosin-binding protein C and cardiac troponin I). Similarly, cardiomyocytes derived from mouse embryonic stem cells atrophied under pre-miR-29 conditioned medium whereas pre-miR-30c conditioned medium had a prohypertrophic effect. Levels of miR-29a, miR-29c and miR-30c but not miR-29b were significantly reduced in a mouse model of pathological but not physiological hypertrophy. Treatment with antagomiRs to miR-29b induced excess fibrosis after aortic constriction without overt deterioration in cardiac function. Conclusions: Our proteomic analysis revealed novel molecular targets of miRNAs that are linked to a fibrogenic cardiac phenotype. Such comprehensive screening methods are essential to define the concerted actions of miRNAs in cardiovascular disease.

Original language	English
Journal	Circulation Research
DOIs	https://doi.org/10.1161/CIRCRESAHA.113.302400
Publication status	E-pub ahead of print - 4 Sept 2013

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Abonnenc, M., Nabeebaccus, A. A., Mayr, U., Barallobre-Barreiro, J., Dong, X., Cuello, F., Sur, S., Drozdov, I., Langley, S., Lu, R., Stathopoulou, K., Didangelos, A., Yin, X., Zimmermann, W. H., Shah, A. M., Zampetaki, A., & Mayr, M. (2013). Extracellular Matrix Secretion by Cardiac Fibroblasts: Role of microRNA-29b and microRNA-30c. Circulation Research. Advance online publication. https://doi.org/10.1161/CIRCRESAHA.113.302400

@article{e687a9a02c144eb8b5dfdadda7183315,

title = "Extracellular Matrix Secretion by Cardiac Fibroblasts: Role of microRNA-29b and microRNA-30c",

abstract = "Rationale: MicroRNAs (miRNAs), in particular miR-29b and miR-30c, have been implicated as important regulators of cardiac fibrosis. Objective: To perform a proteomics comparison of miRNA effects on extracellular matrix (ECM) secretion by cardiac fibroblasts (CFs). Methods and Results: Mouse CFs were transfected with pre-/anti-miR of miR-29b and miR-30c and their conditioned medium was analysed by mass spectrometry. MiR-29b targeted a cadre of proteins involved in fibrosis, including multiple collagens, matrix metalloproteinases, and leukemia inhibitory factor (LIF), insulin-like growth factor-1 (IGF-1) and pentraxin-3, three predicted targets of miR-29b. MiR-29b even attenuated the CF response to TGFβ. In contrast, miR-30c had little effect on ECM production, but opposite effects with regards to LIF and IGF-1. Both miRNAs indirectly affected cardiac myocytes: Upon transfection with pre-miR-29b, the conditioned medium of CFs lost its ability to support adhesion of rat ventricular myocytes and led to a significant reduction of cardiac myocyte proteins (alpha-actinin, cardiac myosin-binding protein C and cardiac troponin I). Similarly, cardiomyocytes derived from mouse embryonic stem cells atrophied under pre-miR-29 conditioned medium whereas pre-miR-30c conditioned medium had a prohypertrophic effect. Levels of miR-29a, miR-29c and miR-30c but not miR-29b were significantly reduced in a mouse model of pathological but not physiological hypertrophy. Treatment with antagomiRs to miR-29b induced excess fibrosis after aortic constriction without overt deterioration in cardiac function. Conclusions: Our proteomic analysis revealed novel molecular targets of miRNAs that are linked to a fibrogenic cardiac phenotype. Such comprehensive screening methods are essential to define the concerted actions of miRNAs in cardiovascular disease.",

author = "Melanie Abonnenc and Nabeebaccus, {Adam A} and Ursula Mayr and Javier Barallobre-Barreiro and Xuebin Dong and Friederike Cuello and Sumon Sur and Ignat Drozdov and Sarah Langley and Ruifang Lu and Konstantina Stathopoulou and Athanasios Didangelos and Xiaoke Yin and Zimmermann, {Wolfram H} and Shah, {Ajay M} and Anna Zampetaki and Manuel Mayr",

year = "2013",

month = sep,

day = "4",

doi = "10.1161/CIRCRESAHA.113.302400",

language = "English",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "Lippincott Williams and Wilkins",

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Abonnenc, M , Nabeebaccus, AA , Mayr, U , Barallobre-Barreiro, J , Dong, X , Cuello, F, Sur, S, Drozdov, I , Langley, S , Lu, R , Stathopoulou, K , Didangelos, A , Yin, X, Zimmermann, WH, Shah, AM , Zampetaki, A & Mayr, M 2013, 'Extracellular Matrix Secretion by Cardiac Fibroblasts: Role of microRNA-29b and microRNA-30c', Circulation Research. https://doi.org/10.1161/CIRCRESAHA.113.302400

TY - JOUR

T1 - Extracellular Matrix Secretion by Cardiac Fibroblasts

T2 - Role of microRNA-29b and microRNA-30c

AU - Abonnenc, Melanie

AU - Nabeebaccus, Adam A

AU - Mayr, Ursula

AU - Barallobre-Barreiro, Javier

AU - Dong, Xuebin

AU - Cuello, Friederike

AU - Sur, Sumon

AU - Drozdov, Ignat

AU - Langley, Sarah

AU - Lu, Ruifang

AU - Stathopoulou, Konstantina

AU - Didangelos, Athanasios

AU - Yin, Xiaoke

AU - Zimmermann, Wolfram H

AU - Shah, Ajay M

AU - Zampetaki, Anna

AU - Mayr, Manuel

PY - 2013/9/4

Y1 - 2013/9/4

N2 - Rationale: MicroRNAs (miRNAs), in particular miR-29b and miR-30c, have been implicated as important regulators of cardiac fibrosis. Objective: To perform a proteomics comparison of miRNA effects on extracellular matrix (ECM) secretion by cardiac fibroblasts (CFs). Methods and Results: Mouse CFs were transfected with pre-/anti-miR of miR-29b and miR-30c and their conditioned medium was analysed by mass spectrometry. MiR-29b targeted a cadre of proteins involved in fibrosis, including multiple collagens, matrix metalloproteinases, and leukemia inhibitory factor (LIF), insulin-like growth factor-1 (IGF-1) and pentraxin-3, three predicted targets of miR-29b. MiR-29b even attenuated the CF response to TGFβ. In contrast, miR-30c had little effect on ECM production, but opposite effects with regards to LIF and IGF-1. Both miRNAs indirectly affected cardiac myocytes: Upon transfection with pre-miR-29b, the conditioned medium of CFs lost its ability to support adhesion of rat ventricular myocytes and led to a significant reduction of cardiac myocyte proteins (alpha-actinin, cardiac myosin-binding protein C and cardiac troponin I). Similarly, cardiomyocytes derived from mouse embryonic stem cells atrophied under pre-miR-29 conditioned medium whereas pre-miR-30c conditioned medium had a prohypertrophic effect. Levels of miR-29a, miR-29c and miR-30c but not miR-29b were significantly reduced in a mouse model of pathological but not physiological hypertrophy. Treatment with antagomiRs to miR-29b induced excess fibrosis after aortic constriction without overt deterioration in cardiac function. Conclusions: Our proteomic analysis revealed novel molecular targets of miRNAs that are linked to a fibrogenic cardiac phenotype. Such comprehensive screening methods are essential to define the concerted actions of miRNAs in cardiovascular disease.

AB - Rationale: MicroRNAs (miRNAs), in particular miR-29b and miR-30c, have been implicated as important regulators of cardiac fibrosis. Objective: To perform a proteomics comparison of miRNA effects on extracellular matrix (ECM) secretion by cardiac fibroblasts (CFs). Methods and Results: Mouse CFs were transfected with pre-/anti-miR of miR-29b and miR-30c and their conditioned medium was analysed by mass spectrometry. MiR-29b targeted a cadre of proteins involved in fibrosis, including multiple collagens, matrix metalloproteinases, and leukemia inhibitory factor (LIF), insulin-like growth factor-1 (IGF-1) and pentraxin-3, three predicted targets of miR-29b. MiR-29b even attenuated the CF response to TGFβ. In contrast, miR-30c had little effect on ECM production, but opposite effects with regards to LIF and IGF-1. Both miRNAs indirectly affected cardiac myocytes: Upon transfection with pre-miR-29b, the conditioned medium of CFs lost its ability to support adhesion of rat ventricular myocytes and led to a significant reduction of cardiac myocyte proteins (alpha-actinin, cardiac myosin-binding protein C and cardiac troponin I). Similarly, cardiomyocytes derived from mouse embryonic stem cells atrophied under pre-miR-29 conditioned medium whereas pre-miR-30c conditioned medium had a prohypertrophic effect. Levels of miR-29a, miR-29c and miR-30c but not miR-29b were significantly reduced in a mouse model of pathological but not physiological hypertrophy. Treatment with antagomiRs to miR-29b induced excess fibrosis after aortic constriction without overt deterioration in cardiac function. Conclusions: Our proteomic analysis revealed novel molecular targets of miRNAs that are linked to a fibrogenic cardiac phenotype. Such comprehensive screening methods are essential to define the concerted actions of miRNAs in cardiovascular disease.

U2 - 10.1161/CIRCRESAHA.113.302400

DO - 10.1161/CIRCRESAHA.113.302400

M3 - Article

C2 - 24006456

SN - 0009-7330

JO - Circulation Research

JF - Circulation Research

ER -

Extracellular Matrix Secretion by Cardiac Fibroblasts: Role of microRNA-29b and microRNA-30c

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