Biology subjects

Rajagopalan, V.

Publications and source records attributed to Rajagopalan, V..

3 recordsLinked to original sources

bioRxiv2026

Novel Cardiometabolic Factors Regulate Neurite Outgrowth in Cancer Chemotherapy-Induced Cardiotoxicity

BackgroundCardiovascular diseases and cancer are the leading causes of death in the United States and worldwide. Although various therapies against cancer improve patient survival, cardiotoxicity remains a life-threatening adverse outcome, with emerging evidence of downstream effects, including neural dysfunction. While autonomic regulation of the cardiovascular system is well-studied, regulation of the nervous system by the heart is not fully clear. We hypothesized that cardiac cells secrete non-canonical paracrine metabolic factors that support neuronal growth and function, and chemotherapy disrupts this signaling. MethodsWe employed co- culture models of the well-established H9C2 cardiac and PC12 neuronal cell lines and human induced pluripotent stem cells (hiPSCs), and assessed them with molecular, omic, biochemical, morphological, physiological, and pharmacological assays. ResultsHealthy H9C2 cells robustly induced PC12 neurite outgrowth (neurite length and number of neurite-bearing cells) both directly (with cellular contact) and indirectly (only conditioned media), whereas doxorubicin-exposed H9C2 cells failed to produce this effect. Recently approved anti-cancer agents (2020 or later) also reduced or attenuated cardiac cell-induced outgrowth. Untargeted metabolomic analysis of conditioned media revealed multiple novel potential neurite-promoting factors, and pharmacologically inhibiting them significantly reduced PC12 neurite outgrowth. The analysis also identified distinct metabolites that were differentially regulated following doxorubicin exposure. These findings were further supported in a hiPSC-based model, in which conditioned media from doxorubicin-injured hiPSC cardiomyocytes reduced {beta}III-tubulin intensity and norepinephrine secretion in hiPSC-derived sympathetic neurons. ConclusionTogether, these findings unravel a new line of research on cardio-neuronal communication and reveal novel metabolic targets that may inform future strategies to mitigate neurotoxicity induced by chemotherapy-associated cardiac injury.

Cell Biology↗

bioRxiv2026

β2-Adrenergic Signaling Switches from Cardioprotective to Cardiotoxic in Acute vs. Chronic Oxidative Stress

BACKGROUND AND PURPOSE{beta}-adrenergic receptors (AR) regulate both cardiac function and remodeling. Many studies suggest that, in addition to their effects on heart rate and contractility, {beta}1-ARs mediate cardiotoxic signaling, whereas {beta}2-ARs are generally cardioprotective. However, there is conflicting data on the role of {beta}2-ARs, differing dependent on the nature of the stress. Given the extremely common use of {beta}-blockers and agonists clinically, we sought to understand the differential cardioprotective/cardiotoxic effects of {beta}2-AR signaling dependent on timing (acute vs. chronic) and type of cardiotoxic stress. EXPERIMENTAL APPROACHWild-type (WT) and {beta}-AR knockout ({beta}1-KO and {beta}2-KO) mice were subjected to acute (15 mg{middle dot}kg-1 x 1 dose) or chronic (2 mg{middle dot}kg-1{middle dot}wk-1 x 7 wks) oxidative stress using doxorubicin (DOX). Survival, cardiac function and histopathology were assessed and differential signaling activation determined by Western blot and gene expression by RNA-seq. KEY RESULTSWe have shown that {beta}2-KOs manifest extreme cardiotoxicity with acute DOX (100% mortality within 30 min), supporting a strong cardioprotective role of {beta}2-signaling. In marked contrast, with chronic DOX, {beta}2-KO had enhanced survival (t[1/2] 54 d vs. 42 d in WT) and attenuated cardiac dysfunction. In {beta}2-KO, acute DOX activated stress MAPKs (p38, ERK and JNK), whereas chronic DOX did not; furthermore, in the absence of {beta}2-ARs, oxidative stress and lipid accumulation were reduced, genes regulating compensatory metabolic pathways (AMPK and insulin/PI3K) were upregulated, and genes regulating mitochondrial and contractile function were preserved, whereas they were downregulated in WT with chronic DOX. CONCLUSIONS{beta}2-AR signaling switches from being cardioprotective during acute oxidative stress, to cardiotoxic during chronic stress. Inhibition of {beta}2-AR signaling during chronic stress induces signaling and metabolic compensations that serve to reduce oxidative injury. This unexpected temporal switching has potential significant implications for all models of cardiovascular disease, as well as for the clinical use of subtype-specific {beta}-blockers. CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABSO_LIOur finding that {beta}2-adrenergic receptor signaling can switch from being beneficial (cardioprotective) to detrimental (cardiotoxic) depending on the acuteness or chronicity of a cardiac stressor. C_LIO_LIIdentification of the mechanisms by which this temporal switch is mediated could lead to new drug development. C_LI What are the clinical implications?O_LIOur findings provide potential guidance in choosing between a {beta}1-specific vs. a {beta}1/2-non-specific drug when treating specific cardiovascular diseases based on their temporal characteristics. C_LIO_LIThe temporal protective/toxic switching that we describe could be a mechanism common to many other drugs, yet is rarely tested, suggesting the need for additional studies using temporal course as a factor. C_LI

cell biology↗

bioRxiv2025

Noncoding and Coding Mechanisms of Aging Heart Failure with Preserved Ejection Fraction with Thyroid Dysfunction

Heart Failure with preserved Ejection Fraction (HFpEF) is a heterogeneous geriatric syndrome with complex pathophysiology and comorbidities. Long noncoding RNAs (lncRNAs) account for a large majority of the functional mammalian transcriptome and act as key regulators in complex physiological and pathological processes. However, the role of lncRNAs and the development of thyroid dysfunction in aging HFpEF is not clear. We investigated the ZSF1 model in both early and more severe stages of HFpEF (5-, 13- and 20-months old [mo]). We assessed molecular, biochemical, and pathophysiological roles involving lncRNAs, mRNAs, and inflammatory markers. Thyroid hormone (TH) immuno-sorbent assays showed significant decreases in serum T3 levels in 5-mo and serum T4 levels in 5-mo and 13-mo obese HFpEF groups compared to lean controls. Morphometric analyses showed significant increases in heart and LV weights in obese HFpEF rats indicating cardiac hypertrophy. LncRNA microarray and RT-qPCR revealed that three key lncRNAs were significantly increased in 13-mo obese HFpEF but not in 5-mo obese HFpEF left ventricles compared to the ZSF1 lean controls. Microarray analyses showed that Sik1 mRNA was significantly upregulated and Anxa13 was downregulated in early obese HFpEF hearts compared to the lean controls. Additionally, we also uncovered previously unreported tissue and serum inflammatory cytokine profiles in early and late HFpEF. This study has identified key novel lncRNA and inflammatory markers in early and late hypothyroid HFpEF. Further studies may help in better understanding and development of diagnostic and therapeutic targets for HFpEF that presents with severe morbidity and mortality.

genomics↗