This conformational change exposes a large hydrophobic pocket between helix 3, 4, and the hinge region of S100A1 that is involved in virtually all calcium-dependent target protein interactions.

[27] In a rat model of myocardial infarction, intracoronary S100A1 adenoviral gene transfer restored sarcoplasmic reticular calcium transients and load, normalized intracellular sodium concentrations, reversed the pathologic expression of the fetal gene program, restored energy supply, normalized contractile function, preserved inotropic reserve, and reduced cardiac hypertrophy 1 week post-myocardial infarction.

[28][29] In support of the adenoviral experiments, S100A1 transgenic overexpressing mice subjected to myocardial infarction showed preserved contractile function, abrogated apoptosis, preserved sarcoplasmic reticulum calcium cycling and beta adrenergic signaling, prevention from cardiac hypertrophy and heart failure, as well as prolonged survival relative to non-transgenic controls.

[30][31] S100A1 has also been identified as a novel regulator of endothelial cell post-ischemic angiogenesis, as patients with limb ischemia exhibited downregulation of S100A1 expression in hypoxic tissue.

[34] S100A1 has shown efficacy in feasibility in treating heart failure symptoms in large, preclinical models and human cardiomyocytes,[35][36] and thus shows great promise for clinical trials.

[37][38][39][40][41][42][43] Reduced expression of this protein has been implicated in cardiomyopathies,[44] and left ventricular assist device-based therapy does not restore S100A1 levels in patients.

[45] S100A1 has shown promise as an early diagnostic biomarker for acute myocardial ischemia, presenting with a distinct timecourse in human plasma following an ischemic event relative to traditional markers creatine kinase, CKMB and troponin I.

[46][47] This injury-released, extracellular pool of S100A1 was investigated in neonatal murine cardiomyocytes and was shown to prevent apoptosis via an ERK1/2-dependent pathway, suggesting that the release of S100A1 from injured cells is an intrinsic survival mechanism for viable myocardium.