Biology subjects

Hemanthakumar, K. A.

Publications and source records attributed to Hemanthakumar, K. A..

3 recordsLinked to original sources

bioRxiv2022

STAT5b is a key effector of NRG-1/ERBB4-mediated cardiomyocyte growth

The growth factor neuregulin-1 (NRG-1) regulates hypertrophic and hyperplastic myocardial growth and is currently under clinical investigation as a treatment for heart failure. We have previously demonstrated that an isoform of the NRG-1 receptor ERBB4 (ERBB4 JM-b) expressed in cardiomyocytes selectively regulates the activation of STAT5b. To explore the role of STAT5b in NRG-1/EBBB4 mediated cardiomyocyte growth, several in vitro and in vivo models were utilized. The downregulation of NRG-1/ERBB4 signaling consistently reduced STAT5b activation and transcription of STAT5b target genes Igf1, Myc and Cdkn1a in murine in vitro and in vivo models of myocardial growth. Stat5b knock-down in primary cardiomyocytes ablated NRG-1-induced cardiomyocyte hypertrophy. Stat5b was activated during NRG-1-induced hyperplastic myocardial growth and chemical inhibition of the Nrg-1/Erbb4 pathway led to the loss of myocardial growth and Stat5 activation in zebrafish embryos. Moreover, CRISPR/Cas9-mediated knock-down of stat5b in zebrafish embryos resulted in reduced myocardial growth and heart failure as indicated by reduced ventricular ejection fraction. Dynamin-2 was discovered to control the cell surface localization of ERBB4 and the chemical inhibition of dynamin-2 downregulated NRG-1/ERBB4/STAT5b signaling in models of hypertrophic and hyperplastic myocardial growth. Finally, the activation of the NRG-1/ERBB4/STAT5b signaling pathway was explored in clinical samples representing pathological cardiac hypertrophy. The NRG-1/ERBB4/STAT5b signaling pathway was differentially regulated both at the mRNA and protein levels in the myocardium of patients with pathological cardiac hypertrophy as compared to myocardium of control subjects. These results establish the role for STAT5b, and dynamin-2 in NRG-1/ERBB4-mediated myocardial growth.

cell biology↗

bioRxiv2020

Cardiovascular disease risk factors induce mesenchymal features and senescence in cardiac endothelial cells

Aging, obesity, hypertension and physical inactivity are major risk factors for endothelial dysfunction and cardiovascular disease (CVD). We applied fluorescence-activated cell sorting (FACS), RNA sequencing and bioinformatic methods to investigate the common effects of CVD risk factors on cardiac endothelial cells (ECs). Aging, obesity and pressure overload all upregulated pathways related to TGF-{beta} signaling and mesenchymal gene expression, inflammation, vascular permeability, oxidative stress, collagen synthesis and cellular senescence, whereas exercise training downregulated most of the same pathways. We identified collagen chaperone SerpinH1/HSP47 to be significantly increased by aging and obesity and repressed by exercise training. Mechanistic studies demonstrated that SERPINH1/HSP47 in human ECs changed cell morphology and increased mesenchymal gene expression, while its silencing inhibited collagen deposition. Our data demonstrate that CVD risk factors significantly remodel the transcriptomic landscape of cardiac ECs to acquire senescence and mesenchymal features. SERPINH1/HSP47 was identified as a potential therapeutic target in ECs.

molecular biology↗

bioRxiv2020

Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 - implications for microvascular inflammation and hypercoagulopathy in COVID-19 patients

Accumulating clinical observations implicate vascular inflammation as an underlying cause of coagulopathy in severely ill COVID-19 patients and it was recently suggested that SARS-CoV-2 virus particles infect endothelial cells. Here, we show that endothelial cells do not express angiotensin-converting enzyme-2 (ACE2), the SARS-CoV-2 receptor. Instead, pericytes and microvascular smooth muscle cells express ACE2 in an organotypic manner. Pericyte deficiency leads to increased endothelial expression and release of Von Willebrand factor and intravascular platelet and fibrin aggregation, suggesting that pericytes limit endothelial pro-thrombotic responses. That pericytes and not endothelial cells express ACE2 may provide important clues to the pathology of COVID-19, as pericytes are normally shielded behind an endothelial barrier and may get infected only when this barrier is compromised by COVID-19 risk factors.

pathology↗