Biology subjects

Selvaraji, S.

Publications and source records attributed to Selvaraji, S..

3 recordsLinked to original sources

bioRxiv2021

Multiomics Analyses Reveal Dynamic Bioenergetic Pathways and Functional Remodeling of the Heart During Intermittent Fasting

AimsIntermittent fasting (IF) reduces cardiovascular risk factors in animals and humans, and can protect the heart against ischemic injury in models of myocardial infarction, but the underlying molecular mechanisms are unknown. To delineate molecular and cellular adaptations of the heart to IF, we carried out system-wide comprehensive analyses of proteome and phosphoproteome, complemented with transcriptome profiling, followed by functional analysis. Methods and resultsIn order to understand molecular and cellular remodeling of the heart during IF, we employed advanced mass spectrometry for system-wide profiling of the proteome and phosphoproteome of heart tissues obtained from mice maintained for 6 months on either daily 12- or 16-hour fasting, every-other-day fasting or ad libitum control feeding regimens. We also performed transcriptome analyses using RNA sequencing to evaluate whether the observed molecular responses to IF occur at the transcriptional or post-transcriptional levels. IF regimens significantly affected pathways that regulate cyclic GMP signaling, lipid and amino acid metabolism, cell adhesion, cell death, and inflammation. Comparison of differentially expressed proteome and transcriptome upon IF showed the higher correlation of pathway alternation in short IF regimen but the inverse correlation of metabolic processes such as fatty acid oxidation and immune processes in longer IF regimens. In addition, functional echocardiographic analyses demonstrated that IF enhances stress-induced cardiac performance. ConclusionOur systematic multi-omics study elucidates a molecular framework for understanding how IF impacts the hearts function and its vulnerability to injury and disease. Translational perspectiveIntermittent fasting is emerging as a desirable lifestyle adaptation to impact cardiovascular health through the modulation of molecular and cellular mechanisms, and by acting on disease risk factors. Evidence from numerous studies indicates that the fasting cycles are highly and consistently effective in protecting against cardiovascular diseases and improving cardiac health in animals and human. Using multi-omics, here we dissect distinct molecular adaptations of the heart to different intermittent fasting regimens. Our results unveil novel cardioprotective mechanisms and open up new avenues for innovative pharmacological approaches to prevent and treat cardiovascular diseases.

systems biology↗

bioRxiv2020

Hippocampal Transcriptome Profiling Reveals Common Disease Pathways in Chronic Hypoperfusion and Ageing

Vascular dementia (VaD) is a progressive cognitive impairment of vascular etiology. VaD is characterized by cerebral hypoperfusion, increased blood-brain barrier permeability and white matter lesions. An increased burden of VaD is expected due to rapidly aging populations. The hippocampus is particularly susceptible to hypoperfusion, and the resulting memory impairment may play a crucial role in VaD. Here we have investigated the hippocampal gene expression profile of young and old mice subjected to chronic cerebral hypoperfusion by bilateral common carotid artery stenosis (BCAS). Our data in sham-operated young and aged mice show the normal age-associated decline in cerebral blood flow and differential gene expression. BCAS and ageing caused broadly similar effects, however, BCAS-induced changes in hippocampal gene expression differed between young and aged mice. Specifically, transcriptomic analysis indicated that in comparison to young sham mice, many pathways altered by BCAS in young mice resembled those present in sham aged mice. Immunoblot analyses confirmed these findings. Finally, relative to young sham mice the cell type-specific profile of genes in both young BCAS and old sham animals further revealed common cell-specific genes. Our data provide a genetic-based molecular framework for chronic hypoperfusion-induced hippocampal damage and reveal common cellular signaling pathways likely to be important in the pathophysiology of VaD.

neuroscience↗

bioRxiv2020

AIM2 Inflammasome Mediates Hallmark Neuropathological Alterations and Cognitive Impairment in a Mouse Model of Vascular Dementia

Chronic cerebral hypoperfusion is associated with vascular dementia (VaD). Cerebral hypoperfusion may initiate complex molecular and cellular inflammatory pathways that contribute to long-term cognitive impairment and memory loss. Here we used a bilateral common carotid artery stenosis (BCAS) mouse model of VaD to investigate its effect on the innate immune response - particularly the inflammasome signaling pathway. Comprehensive analyses revealed that chronic cerebral hypoperfusion induces a complex temporal expression and activation of inflammasome components and their downstream products (IL-1{beta} and IL-18) in different brain regions, and promotes activation of apoptotic and pyroptotic cell death pathways. Polarized glial cell activation, white matter lesion formation and hippocampal neuronal loss also occurred in a spatiotemporal manner. Moreover, in AIM2 knockout mice we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis and pyroptosis, as well as resistance to chronic microglial activation, myelin breakdown, hippocampal neuronal loss, and behavioural and cognitive deficits following BCAS. Hence, we have demonstrated that activation of the AIM2 inflammasome substantially contributes to the pathophysiology of chronic cerebral hypoperfusion-induced brain injury and may therefore represent a promising therapeutic target for attenuating cognitive impairment in VaD.

neuroscience↗