Cardiomyocytes, Endothelial Cells and Cardiac Fibroblasts: S100A1’s Triple Action in Cardiovascular Pathophysiology

Abstract

Over the past decade, basic and translational research delivered comprehensive evidence for the relevance of the Ca(2+)-binding protein S100A1 in cardiovascular diseases. Aberrant expression levels of S100A1 surfaced as molecular key defects, driving the pathogenesis of chronic heart failure, arterial and pulmonary hypertension, peripheral artery disease and disturbed myocardial infarction healing. Loss of intracellular S100A1 renders entire Ca(2+)-controlled networks dysfunctional, thereby leading to cardiomyocyte failure and endothelial dysfunction. Lack of S100A1 release in ischemic myocardium compromises cardiac fibroblast function, entailing impaired damage healing. This review focuses on molecular pathways and signaling cascades regulated by S100A1 in cardiomyocytes, endothelial cells and cardiac fibroblasts in order to provide an overview of our current mechanistic understanding of S100A1's action in cardiovascular pathophysiology.

Effect of testosterone supplementation on nitroso‐redox imbalance, cardiac metabolism markers, and S100 proteins expression in the heart of castrated male rats

“…In our study, the decrease in S100 proteins immunostaining can reflect a reduced immunoreactivity of S100A1 protein, which is the predominant cardiac S100 protein among other S100 cardiac isoforms (S100A4, S100A6, and S100B). S100A1 is very abundant in cardiomyocyte cytoplasm, it is found in the junctional and longitudinal sarcoplasmic reticulum (with ryanodine receptor (RyR2) and Ca² + ‐ATPase 2a (SERCA2a)‐phospholamban (PLB) complex), at the sarcomere myofilaments (titin) and within mitochondria (F1‐ATPase) (Rohde et al ., ).…”

“…S100A1 is a key regulator of calcium homeostasis during contraction–relaxation cycling and its ability to sense Ca 2+ seems to be dependent on NO post‐translational modification under physiological conditions (Rohde et al ., ). In this study, reduced immunoreactivity of S100 proteins can be attributed to structural damages induced by excessive ROS especially NO.…”

Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease

“…S100P is differentially expressed in PBMCs from IPAH patients (11), and dimerizes with another member of the protein family, S100A1 (12); S100A dimerization appears important for its function in orchestrating cardiomyocyte and endothelial function, as well as cardiac fibroblasts (13). In cardiac endothelial cells, S100A1 is involved in nitric oxide homeostasis, and decreased expression is associated with arterial and pulmonary hypertension (13). Another S100A protein, S100A4, activates advance glycation end-products receptor (RAGE) leading to activation of STAT3 and decreased bone morphogenetic protein receptor-2 (BMPR2) activity in human pulmonary artery smooth muscle cells (14).…”

Inhibition of cardiac CaMKII to cure heart failure: step by step towards translation?

“…In this context, the establishment of a gene therapy approach seems “easier” than the development of pharmacological inhibitors. Also, gene therapy studies in large animals or even patients have already been tested for S100A1, SERCA2a and adenylyl cyclase 6 [ 1 , 11 , 20 , 31 , 33 , 35 , 36 ]. SERCA2a gene therapy has already reached clinical phase IIb studies, but then failed due to insufficient delivery of viral particles to the heart.…”