Biology subjects

Dhandapany, P. S.

Publications and source records attributed to Dhandapany, P. S..

3 recordsLinked to original sources

bioRxiv2026

Cell-autonomous Wnt activity promotes transient re-programming and cell cycle re-entry of coronary artery endothelial cells

Coronary occlusion leads to formation of collateral arteries connecting occluded and perfused arteries. This process, namely artery reassembly, is temporally restricted to the cardiac regenerative window in mice and relies on cell cycle re-entry of post-mitotic artery endothelial cells (ECs). Analyses of single cell RNA sequencing data of ischemic mouse hearts led to identification of Wnt activity in proliferating artery cells. Using mouse genetics and whole organ imaging at cellular resolution, we show that Wntless (Wls)-mediated Wnt secretion and Frizzled (Fzd)4-dependent Wnt reception by artery cells, was essential for development of coronary collaterals. Specifically, Fzd4 promoted proliferation and expression of (progenitor-like) capillary/venous markers in coronary artery ECs. In embryonic hearts, coronary arteries originate from capillaries. Fzd4 in these capillaries was essential for proliferation; depletion of which, accelerated their differentiation into arteries by arterialization. Along these lines, an exogeneous dose of human WNT2-sFRP1 ligand complex reactivated artery cell proliferation and restored artery reassembly in non-regenerative mouse hearts. Thus, ischemia-induced cell-autonomous Wnt signaling promoted developmental reprogramming of coronary artery ECs. Finally, exome sequencing of coronary artery disease patients, revealed unique pathogenic variants of WLS and FZD4. Together, our study provides mechanistic insights into EC plasticity and underscores the significance of WNT pathway in cardiovascular disease.

developmental biology↗

bioRxiv2024

The long non-coding RNA NEAT1 regulates the transcriptional landscape of cardiomyocytes

Long non-coding RNAs (lncRNAs) play a crucial role in fine-tuning the gene expression. In the present study, we identified that the lncRNA NEAT1 is upregulated in failing murine hearts and in human hypertrophic cardiomyopathies. Further investigations demonstrated that NEAT1 expression is regulated by calcium dependent NFAT (nuclear factor of activated T cells). Overexpression of NEAT1 led to increased cardiomyocyte size and elevated expression of cardiac stress markers while its depletion had the opposite effect. Through transcriptomic analysis in NEAT1-KO cells, we demonstrated the cis-regulatory role of NEAT1, wherein it maintains the transcription of neighboring genes by interacting with the coactivator p300. Additionally, NEAT1 depletion resulted in decreased expression of GRK2 (G protein-coupled receptor kinase 2), a key player in the development of cardiac hypertrophy, suggesting that NEAT1 contributes to the development of cardiac hypertrophy by regulating GRK2 expression. Consistent with this, Neat1-/- mice are resistant to {beta}-adrenergic stimulation. Overall, our study provides enough evidence that NEAT1 is a calcium-regulated, pro-hypertrophic lncRNA that exerts significant control over the transcriptional landscape of cardiomyocytes during heart failure.

cell biology↗

bioRxiv2018

Myocardin ablation in a cardiac-renal rat model

Cardiorenal syndrome is defined by primary heart failure conditions influencing or leading to renal injury or dysfunction. Dilated cardiomyopathy (DCM) is a major co-existing form of heart failure (HF) with renal diseases. Myocardin (MYOCD), a cardiac-specific co-activator of serum response factor (SRF), is increased in DCM mice and patient cardiac tissues and plays a crucial role in the pathophysiology of DCM. Inhibiting the increased MYOCD has shown to be partially rescuing the DCM mice phenotype. However, expression levels of MYOCD in the cardiac tissues of the cardiorenal syndromic patients and the beneficial effect of inhibiting MYOCD in a cardiorenal syndrome model remains to be explored. Here, we analyzed the expression levels of MYOCD in the DCM patients with and without renal diseases. We also explored, whether cardiac specific silencing of MYOCD expression could ameliorate the cardiac remodeling and improve cardiac function in a renal artery ligated rat model (RAL). We observed an increase in MYOCD levels in the endomyocardial biopsies of DCM patients associated with renal failure compared to DCM alone. Silencing of MYOCD in RAL rats by a cardiac homing peptide conjugated MYOCD siRNA resulted in attenuation of cardiac hypertrophy, fibrosis and restoration of the left ventricular functions. Our data suggest hyper-activation of MYOCD in the pathogenesis of the cardiorenal failure cases. Also, MYOCD silencing showed beneficial effects by rescuing cardiac hypertrophy, fibrosis, size and function in a cardiorenal rat model.

molecular biology↗