Cardiomyocyte-specific LARP6 overexpression prevents Angiotensin II-induced myocardial dysfunction and interstitial fibrosis
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ABSTRACT:
PROVIDER: PRJNA1198339 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31717439_1.fastq.gz | Fastqsanger.gz | |||
| SRR31717439_2.fastq.gz | Fastqsanger.gz | |||
| SRR31717440_1.fastq.gz | Fastqsanger.gz | |||
| SRR31717440_2.fastq.gz | Fastqsanger.gz | |||
| SRR31717441_1.fastq.gz | Fastqsanger.gz |
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Project description:La ribonucleoprotein 6, Translational Regulator (LARP6), a multifunctional mRNA binding protein with well-described pro-fibrotic effects, increases type I collagen mRNA half-life, translation, and deposition in non-cardiac tissues. In the heart LARP6 is expressed in cardiomyocytes, not primarily involved in fibrosis, where its role is unknown. To investigate the role of cardiomyocyte-derived LARP6 on cardiac function and remodeling, we generated a cardiomyocyte-specific LARP6 overexpressing transgenic mouse model (LARP6-Tg). Baseline longitudinal studies up to 10 months of age revealed that constitutive overexpression of LARP6 had no significant effect on cardiac function or morphology despite inducing mild interstitial fibrosis versus wild-type littermates (WT). Subsequently, we hypothesized that cardiomyocyte-specific LARP6-Tg mice would exhibit exacerbated cardiac remodeling and dysfunction in response to hypertensive stress via angiotensin II (Ang II) infusion. Ang II (1000 ng/kg/min for 21 days) induced hypertension and cardiac hypertrophy in WT and LARP6-Tg mice of both sexes. Unexpectedly, Ang II-induced cardiac dysfunction was prevented in LARP6-Tg mice. Cardiac gene expression profiling predicted increased fibrosis and cardiomyocyte death in Ang II-treated WT mice and inhibition of cardiomyocyte death in Ang II-treated LARP6-Tg mice, versus saline-treated controls. Surprisingly, Ang II-induced interstitial fibrosis was reduced in LARP6-Tg mice and associated with attenuation of cardiomyocyte cell death and reduced myofibroblast activation. These data support a mild pro-fibrotic action of cardiomyocyte LARP6 in unstressed mice and, paradoxically, that LARP6 overexpression is sufficient to prevent Ang II-induced cardiac interstitial fibrosis and dysfunction. Sustained induction of LARP6 has therapeutic potential in hypertensive heart disease.
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Project description:Purpose: Triple-negative breast cancer (TNBC) has the highest mortality rate of all breast cancer subtypes and currently lacks effective targeted therapies. LARP6 is an RNA-binding protein associated with cancer promotion, but its mechanism of action in TNBC remains unclear. Methods: Firstly, Western blot (WB) was used to detect the expression level of LARP6 protein in TNBC cell lines. The effects of LARP6 overexpression on TNBC cell proliferation and invasion were determined through Cell Counting Kit-8 (CCK-8) and Transwell experiments. Next, RNA sequencing (RNA-seq) and improved RNA immunoprecipitation and sequencing (iRIP-seq) were performed to analyze LARP6-bound and regulated differentially expressed genes (DEGs) and alternative splicing (AS) events in MDA-MB-231 cells. Finally, RT-qPCR and RIP-qPCR were used for confirmation. Result：Our study found that the overexpressed LARP6 TNBC cell lines significantly promoted thetumor cell proliferation and invasion of cancer (P<0.05). RNA-seq showed that LARP6 overexpression alteredaffected the expression levels of 171 genes, whileand combined with iRIP-seq, it revealedshowed that only EGR1 and LARP6 were bounddirectly bind to by the LARP6 protein, indicating. This shows that LARP6 hasis a weak ability to bind to and regulate differential expression of in regulating genes expression. However, the number of regulatedrelated alternative splicing evensgenes (RASEGs) was upwards ofreached more than 1000, and the correspondingthese genes (RASGs) were mainly enriched in important pathways such as DNA repair and cellular response to DNA damage stimulus. In addition, bassaed on binding peak calling of iRIP-seq in both IP samples,Through analysis of binding peaks, we found that there were 321 overlapping binding peaks in both IP samples between IP1 and IP2 samples awere identified, in whichnd the genes they were mainly concentrated in the post-transcriptional regulatory pathway, and it was also found that LARP6 might tend to bind motif. The top 5 binding motifs were obtained using HOMER, among which CGACGAG was the binding motifsequence that appeared simultaneously in both IP groups. The intersection of binding peak-related genes andwith RASGs suggestedrevealed that LARP6 could bind to 16 genes and regulate their alternative splicing, thus playing an important role in TNBC progression. directly bind to LARP6, most of which were related to cell proliferation, invasion and drug resistance. Conclusion: We revealed the mechanism that LARP6 promotes TNBC by directly regulating the AS of related genes, which provides a new clue for the targeted therapy of TNBC.
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Project description:Purpose: Triple-negative breast cancer (TNBC) has the highest mortality rate of all breast cancer subtypes and currently lacks effective targeted therapies. LARP6 is an RNA-binding protein associated with cancer promotion, but its mechanism of action in TNBC remains unclear. Methods: Firstly, Western blot (WB) was used to detect the expression level of LARP6 protein in TNBC cell lines. The effects of LARP6 overexpression on TNBC cell proliferation and invasion were determined through Cell Counting Kit-8 (CCK-8) and Transwell experiments. Next, RNA sequencing (RNA-seq) and improved RNA immunoprecipitation and sequencing (iRIP-seq) were performed to analyze LARP6-bound and regulated differentially expressed genes (DEGs) and alternative splicing (AS) events in MDA-MB-231 cells. Finally, RT-qPCR and RIP-qPCR were used for confirmation. Result：Our study found that the overexpressed LARP6 TNBC cell lines significantly promoted thetumor cell proliferation and invasion of cancer (P<0.05). RNA-seq showed that LARP6 overexpression alteredaffected the expression levels of 171 genes, whileand combined with iRIP-seq, it revealedshowed that only EGR1 and LARP6 were bounddirectly bind to by the LARP6 protein, indicating. This shows that LARP6 hasis a weak ability to bind to and regulate differential expression of in regulating genes expression. However, the number of regulatedrelated alternative splicing evensgenes (RASEGs) was upwards ofreached more than 1000, and the correspondingthese genes (RASGs) were mainly enriched in important pathways such as DNA repair and cellular response to DNA damage stimulus. In addition, bassaed on binding peak calling of iRIP-seq in both IP samples,Through analysis of binding peaks, we found that there were 321 overlapping binding peaks in both IP samples between IP1 and IP2 samples awere identified, in whichnd the genes they were mainly concentrated in the post-transcriptional regulatory pathway, and it was also found that LARP6 might tend to bind motif. The top 5 binding motifs were obtained using HOMER, among which CGACGAG was the binding motifsequence that appeared simultaneously in both IP groups. The intersection of binding peak-related genes andwith RASGs suggestedrevealed that LARP6 could bind to 16 genes and regulate their alternative splicing, thus playing an important role in TNBC progression. directly bind to LARP6, most of which were related to cell proliferation, invasion and drug resistance. Conclusion: We revealed the mechanism that LARP6 promotes TNBC by directly regulating the AS of related genes, which provides a new clue for the targeted therapy of TNBC.
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Project description:Treatment of multiple myeloma (MM) with the second-generation proteasome inhibitor (PI) carfilzomib (CFZ) is associated with higher incidence of cardiovascular adverse events compared to first-generation PI bortezomib (BTZ). CFZ and BTZ inhibit the individual proteasome subunits beta1, beta2 and beta5 differently, leading to changes in the degree of functional proteasome inhibition. It is unclear, whether CFZ-induced cardiotoxicity is the result of proteasome inhibition, or an off-target effect. With an unbiased multi-omics approach in conjunction with proteasome subunit-specific inhibitors, we show that CFZ-type 5+2 proteasome subunit inhibition, in contrast to the BTZ-type 5+1 inhibition, directly interferes with cardiomyocyte contractility in vitro and in vivo. CFZ-treated cardiomyocytes showed impaired accumulation of proteins related to ATP production and oxidative metabolism. Single-cell transcriptomic analysis of CFZ-treated murine hearts revealed cardiomyocyte-specific changes leading to impaired cardiac contraction. Metabolic profiling revealed increased levels of cardiac Angiotensin A and nucleoside depletion after CFZ treatment. Angiotensin II Type 1 receptor (AGT1R) inhibitors, all-trans retinoic acid (atRA) or supplementation of soluble amino acids rescued cardiomyocytes from CFZ-induced toxicity in human and murine models in vitro, while they ameliorated the cardiotoxic phenotype in vivo. Our data suggests a novel mechanism for PI-induced cardiotoxicity that reflects clinical findings in which CFZ-type 5+2 proteasome inhibition, in contrast to 5+1 co-inhibition of BTZ, directly interferes with the contractile activity of cardiomyocytes.
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