ORCID Profile
0000-0002-0337-4417
Current Organisation
Baker IDI Heart and Diabetes Institute
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2021
DOI: 10.1161/HYPERTENSIONAHA.121.17384
Abstract: MicroRNA miR-181a is downregulated in the kidneys of hypertensive patients and hypertensive mice. In vitro, miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here, we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a KO (knockout) mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radiotelemetry probes were implanted in 12-week-old C57BL/6J WT (wild type) and miR-181a/b-1 KO mice. Systolic and diastolic BP were 4- to 5-mm Hg higher in KO compared with WT mice over 24 hours ( P .01). Compared with WT mice, renal renin was higher in the juxtaglomerular cells of KO mice. BP was similar in WT mice on a high- (3.1%) versus low- (0.3%) sodium diet (+0.4±0.8 mm Hg), but KO mice showed salt sensitivity (+3.3±0.8 mm Hg P .001). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA sequencing in 6699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4 , Col4a1 , Cd81 , Flt3l , Cxcl16 , and Smad4 . We observed upregulation of pathways related to the immune system, inflammatory response, reactive oxygen species, and nerve development, consistent with higher tyrosine hydroxylase in the kidney. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.
Publisher: Portland Press Ltd.
Date: 12-2020
DOI: 10.1042/BST20191255
Abstract: Single-cell transcriptomics enables inference of context-dependent phenotypes of in idual cells and determination of cellular ersity of complex tissues. Cardiac fibrosis is a leading factor in the development of heart failure and a major cause of morbidity and mortality worldwide with no effective treatment. Single-cell RNA-sequencing (scRNA-seq) offers a promising new platform to identify new cellular and molecular protagonists that may drive cardiac fibrosis and development of heart failure. This review will summarize the application scRNA-seq for understanding cardiac fibrosis and development of heart failure. We will also discuss some key considerations in interpreting scRNA-seq data and some of its limitations.
Publisher: Cold Spring Harbor Laboratory
Date: 27-03-2022
DOI: 10.1101/2022.03.24.485542
Abstract: Coronary microvascular dysfunction (CMD) is associated with cardiac dysfunction and predictive of cardiac mortality in obesity, especially in females. Emerging evidence suggests development of heart failure with preserved ejection fraction in females with CMD and that mineralocorticoid receptor (MR) antagonism may be more efficacious in obese female, versus male, HFpEF patients. Accordingly, we examined the hypothesis that smooth muscle cell (SMC)-specific MR deletion prevents obesity-associated coronary and cardiac diastolic dysfunction in females. Obesity was induced in female mice via western diet (WD) feeding alongside littermates fed standard diet. Initial studies revealed that global MR blockade with spironolactone prevented impaired coronary vasodilation and diastolic dysfunction in obese females. Importantly, specific deletion of SMC-MR similarly prevented obesity-associated coronary and cardiac dysfunction. Cardiac gene expression profiling suggested reduced cardiac inflammation in WD-fed mice with SMC-MR deletion independent of blood pressure, aortic stiffening, and cardiac hypertrophy. Further mechanistic studies utilizing single-cell RNA sequencing of non-cardiomyocyte cell populations revealed novel impacts of SMC-MR deletion on the cardiac cellulome in obese mice. Specifically, WD feeding induced inflammatory gene signatures in multiple non-myocyte populations (B/T cells, macrophages, and endothelium), independent of cardiac fibrosis, that was prevented by SMC-MR deletion. Further, SMC-MR deletion induced a basal reduction in cardiac mast cells and prevented WD-induced cardiac pro-inflammatory chemokine expression and leukocyte recruitment. These data reveal a central role for SMC-MR signaling in obesity-associated coronary and cardiac dysfunction thus supporting the emerging paradigm of a vascular origin of cardiac dysfunction in obesity.
Publisher: Cold Spring Harbor Laboratory
Date: 25-11-2019
DOI: 10.1101/854026
Abstract: Cardiac fibrosis is a key antecedent to many types of cardiac dysfunction including heart failure. Physiological factors leading to cardiac fibrosis have been recognized for decades. However, the specific cellular and molecular mediators that drive cardiac fibrosis, and the relative impact of disparate cell populations on cardiac fibrosis, remain unclear. We developed a novel cardiac single-cell transcriptomics strategy to characterize the cardiac cellulome—the network of cells that forms the heart. This method was utilized to profile the cardiac cellular ecosystem in response to two weeks of continuous administration of Angiotensin II, a pro-fibrotic stimulus which drives pathological cardiac remodeling. This analysis uncovered multiple cell populations contributing to pathological remodeling of the extracellular matrix of the heart. Two phenotypically distinct fibroblast populations emerged after induction of tissue stress to promote fibrosis in the absence of smooth muscle actin-expressing myofibroblasts, a key pro-fibrotic cell population. Further, the cellular responses to Angiotensin II and the relative abundance of fibrogenic cells were sexually dimorphic. These results offer a valuable resource for exploring the cardiac cellular landscape in health and after chronic cardiovascular stress. These data provide insights into the cellular and molecular mechanisms that promote pathological remodeling of the mammalian heart, highlighting early transcriptional changes which precede chronic cardiac fibrosis.
Publisher: Portland Press Ltd.
Date: 17-03-2021
Publisher: Cold Spring Harbor Laboratory
Date: 19-07-2021
DOI: 10.1101/2021.07.18.452862
Abstract: Mammalian cardiovascular tissues are comprised of complex and erse collections of cells. Recent advances in single-cell profiling technologies have accelerated our understanding of tissue cellularity and the molecular networks that orchestrate cardiovascular development, maintain homeostasis, and are disrupted in pathological states. Despite the rapid development and application of these technologies, many cardiac single-cell functional genomics datasets remain inaccessible for most cardiovascular biologists. Access to custom visual representations of the data, including querying changes in cellular phenotypes and interactions in erse contexts, remains unavailable in publicly accessible data portals. Visualizing data is also challenging for scientists without expertise in processing single-cell genomic data. Here we present CLARA—CardiovascuLAR Atlas—a web portal facilitating exploration of the cardiovascular cellular landscape. Using mouse and human single-cell transcriptomic datasets, CLARA enables scientists unfamiliar with single-cell-omic data analysis approaches to examine gene expression patterns and the cell population dynamics of cardiac cells in a range of contexts. The web-application also enables investigation of intercellular interactions that form the cardiac cellular niche. CLARA is designed for ease-of-use and we anticipate that the portal will aid deeper exploration of cardiovascular cellular landscapes in the context of development, homeostasis and disease. CLARA is freely available at clara.baker.edu.au .
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-10-2020
DOI: 10.1161/CIRCULATIONAHA.119.045115
Abstract: Cardiac fibrosis is a key antecedent to many types of cardiac dysfunction including heart failure. Physiological factors leading to cardiac fibrosis have been recognized for decades. However, the specific cellular and molecular mediators that drive cardiac fibrosis, and the relative effect of disparate cell populations on cardiac fibrosis, remain unclear. We developed a novel cardiac single-cell transcriptomic strategy to characterize the cardiac cellulome, the network of cells that forms the heart. This method was used to profile the cardiac cellular ecosystem in response to 2 weeks of continuous administration of angiotensin II, a profibrotic stimulus that drives pathological cardiac remodeling. Our analysis provides a comprehensive map of the cardiac cellular landscape uncovering multiple cell populations that contribute to pathological remodeling of the extracellular matrix of the heart. Two phenotypically distinct fibroblast populations, Fibroblast- Cilp and Fibroblast- Thbs4 , emerged after induction of tissue stress to promote fibrosis in the absence of smooth muscle actin–expressing myofibroblasts, a key profibrotic cell population. After angiotensin II treatment, Fibroblast- Cilp develops as the most abundant fibroblast subpopulation and the predominant fibrogenic cell type. Mapping intercellular communication networks within the heart, we identified key intercellular trophic relationships and shifts in cellular communication after angiotensin II treatment that promote the development of a profibrotic cellular microenvironment. Furthermore, the cellular responses to angiotensin II and the relative abundance of fibrogenic cells were sexually dimorphic. These results offer a valuable resource for exploring the cardiac cellular landscape in health and after chronic cardiovascular stress. These data provide insights into the cellular and molecular mechanisms that promote pathological remodeling of the mammalian heart, highlighting early transcriptional changes that precede chronic cardiac fibrosis.
Publisher: Oxford University Press (OUP)
Date: 05-01-2017
DOI: 10.1093/BIOINFORMATICS/BTW833
Abstract: RNA-seq has become the technology of choice for interrogating the transcriptome. However, most methods for RNA-seq differential expression (DE) analysis do not utilize prior knowledge of biological networks to detect DE genes. With the increased availability and quality of biological network databases, methods that can utilize this prior knowledge are needed and will offer biologists with a viable, more powerful alternative when analyzing RNA-seq data. We propose a three-state Markov Random Field (MRF) method that utilizes known biological pathways and interaction to improve sensitivity and specificity and therefore reducing false discovery rates (FDRs) when detecting differentially expressed genes from RNA-seq data. The method requires normalized count data (e.g. in Fragments or Reads Per Kilobase of transcript per Million mapped reads (FPKM/RPKM) format) as its input and it is implemented in an R package pathDESeq available from Github. Simulation studies demonstrate that our method outperforms the two-state MRF model for various s le sizes. Furthermore, for a comparable FDR, it has better sensitivity than DESeq, EBSeq, edgeR and NOISeq. The proposed method also picks more top Gene Ontology terms and KEGG pathways terms when applied to real dataset from colorectal cancer and hepatocellular carcinoma studies, respectively. Overall, these findings clearly highlight the power of our method relative to the existing methods that do not utilize prior knowledge of biological network. As an R package at github.com/MalathiSIDona athDESeq install_github("MalathiSIDona athDESeq",build_vignettes = TRUE). After installation, type vignette("pathDESeq") to access the vignette. Supplementary data are available at Bioinformatics online.
Publisher: Cold Spring Harbor Laboratory
Date: 13-03-2022
DOI: 10.1101/2022.03.12.480450
Abstract: Cardiovascular disease is one of the most significant causes of death globally, especially in regions where unhealthy diets are prevalent and dietary fibre intake is low. 1,2 Fibre, particularly prebiotic types that feed gut microbes, is essential for maintaining healthy gut microbial ecosystems. 3 One assumption has been that cardiovascular health relates directly to lifestyle choices in adult life. Here, we show in mice that some of these benefits operate from the prenatal stage and relate to the diet and gut microbiome of the mother. Intake of fibre during pregnancy shaped the mothers’ gut microbiome, which had a lasting founding effect on the offspring’s microbial composition and function. Maternal fibre intake during pregnancy significantly changed the cardiac cellular and molecular landscape in the offspring, protecting them against the development of cardiac hypertrophy, remodelling, and inflammation. These suggest a role for foetal exposure to maternal-derived gut microbial metabolites, which are known to cross the placenta and drive epigenetic changes. Maternal fibre intake led to foetal epigenetic reprogramming of the atrial natriuretic peptide gene ( Nppa ), protective against heart failure. These results underscore the importance of dietary intake and the gut microbiome of the mother during pregnancy for cardiovascular disease in the offspring.
Publisher: Cold Spring Harbor Laboratory
Date: 19-03-2021
DOI: 10.1101/2021.03.18.436092
Abstract: MicroRNA miR-181a is down-regulated in the kidneys of hypertensive patients and hypertensive mice. In vitro , miR-181a is a posttranslational inhibitor of renin expression, but pleiotropic mechanisms by which miR-181a may influence blood pressure (BP) are unknown. Here we determined whether deletion of miR-181a/b-1 in vivo changes BP and the molecular mechanisms involved at the single-cell level. We developed a knockout mouse model lacking miR-181a/b-1 genes using CRISPR/Cas9 technology. Radio-telemetry probes were implanted in twelve-week-old C57BL/6J wild-type and miR-181a/b-1 knockout mice. Systolic and diastolic BP were 4-5mmHg higher in knockout compared with wild-type mice over 24-hours ( P . 01 ). Compared with wild-type mice, renal renin was higher in the juxtaglomerular cells of knockout mice. BP was similar in wild-type mice on a high (3.1%) versus low (0.3%) sodium diet (+0.4±0.8mmHg) but knockout mice showed salt sensitivity (+3.3±0.8mmHg, P . 001 ). Since microRNAs can target several mRNAs simultaneously, we performed single-nuclei RNA-sequencing in 6,699 renal cells. We identified 12 distinct types of renal cells, all of which had genes that were dysregulated. This included genes involved in renal fibrosis and inflammation such as Stat4, Col4a1, Cd81, Flt3l, Cxcl16, Smad4 . We observed up-regulation of pathways related to the immune system, inflammatory response, reactive oxygen species and nerve development, consistent with higher tyrosine hydroxylase. In conclusion, downregulation of the miR-181a gene led to increased BP and salt sensitivity in mice. This is likely due to an increase in renin expression in juxtaglomerular cells, as well as microRNA-driven pleiotropic effects impacting renal pathways associated with hypertension.
No related grants have been discovered for Malathi Imiyage Dona.