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The myriad essential roles of microRNAs in cardiovascular homeostasis and disease.

ABSTRACT: According to the World Health Organization, cardiovascular disease accounts for approximately 30% of all deaths in the United States, and is the worldwide leading cause of morbidity and mortality. Over the last several years, microRNAs have emerged as critical regulators of physiological homeostasis in multiple organ systems, including the cardiovascular system. The focus of this review is to provide an overview of the current state of knowledge of the molecular mechanisms contributing to the multiple causes of cardiovascular disease with respect to regulation by microRNAs. A major challenge in understanding the roles of microRNAs in the pathophysiology of cardiovascular disease is that cardiovascular disease may arise from perturbations in intracellular signaling in multiple cell types including vascular smooth muscle and endothelial cells, cardiac myocytes and fibroblasts, as well as hepatocytes, pancreatic β-cells, and others. Additionally, perturbations in intracellular signaling cascades may also have profound effects on heterocellular communication via secreted cytokines and growth factors. There has been much progress in recent years to identify the microRNAs that are both dysregulated under pathological conditions, as well as the signaling pathway(s) regulated by an individual microRNA. The goal of this review is to summarize what is currently known about the mechanisms whereby microRNAs maintain cardiovascular homeostasis and to attempt to identify some key unresolved questions that require further study.

SUBMITTER: Neppl RL

PROVIDER: S-EPMC4200483 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Mitochondrial dysfunction has been implicated in the pathologies of a number of retinal degenerative diseases in both the outer and inner retina. In the outer retina, photoreceptors are particularly vulnerable to mutations affecting mitochondrial function due to their high energy demand and sensitivity to oxidative stress. However, it is unclear how defective mitochondrial biogenesis affects neural development and contributes to neural degeneration. In this report, we investigated the in vivo function of nuclear respiratory factor 1 (Nrf1), a major transcriptional regulator of mitochondrial biogenesis in both proliferating retinal progenitor cells (RPCs) and postmitotic rod photoreceptor cells (PRs). METHODS:We used mouse genetic techniques to generate RPC-specific and rod PR-specific Nrf1 conditional knockout mouse models. We then applied a comprehensive set of tools, including histopathological and molecular analyses, RNA-seq, and electroretinography on these mouse lines to study Nrf1-regulated genes and Nrf1's roles in both developing retinas and differentiated rod PRs. For all comparisons between genotypes, a two-tailed two-sample student's t-test was used. Results were considered significant when P <?0.05. RESULTS:We uncovered essential roles of Nrf1 in cell proliferation in RPCs, cell migration and survival of newly specified retinal ganglion cells (RGCs), neurite outgrowth in retinal explants, reconfiguration of metabolic pathways in RPCs, and mitochondrial morphology, position, and function in rod PRs. CONCLUSIONS:Our findings provide in vivo evidence that Nrf1 and Nrf1-mediated pathways have context-dependent and cell-state-specific functions during neural development, and disruption of Nrf1-mediated mitochondrial biogenesis in rod PRs results in impaired mitochondria and a slow, progressive degeneration of rod PRs. These results offer new insights into the roles of Nrf1 in retinal development and neuronal homeostasis and the differential sensitivities of diverse neuronal tissues and cell types of dysfunctional mitochondria. Moreover, the conditional Nrf1 allele we have generated provides the opportunity to develop novel mouse models to understand how defective mitochondrial biogenesis contributes to the pathologies and disease progression of several neurodegenerative diseases, including glaucoma, age-related macular degeneration, Parkinson's diseases, and Huntington's disease.

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The myriad essential roles of microRNAs in cardiovascular homeostasis and disease.

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