Notch activation enhances lineage commitment and protective signaling in cardiac progenitor cells.

Phase I clinical trials applying autologous progenitor cells to treat heart failure have yielded promising results; however, improvement in function is modest, indicating a need to enhance cardiac stem cell reparative capacity. Notch signaling plays a crucial role in cardiac development, guiding cell fate decisions that underlie myocyte and vessel differentiation. The Notch pathway is retained in the adult cardiac stem cell niche, where level and duration of Notch signal influence proliferation and differentiation of cardiac progenitors.

S100A1 genetically targeted therapy reverses dysfunction of human failing cardiomyocytes.

Objectives: This study investigated the hypothesis whether S100A1 gene therapy can improve pathological key features in human failing ventricular cardiomyocytes (HFCMs).

Background: Depletion of the Ca²⁺-sensor protein S100A1 drives deterioration of cardiac performance toward heart failure (HF) in experimental animal models. Targeted repair of this molecular defect by cardiac-specific S100A1 gene therapy rescued cardiac performance, raising the immanent question of its effects in human failing myocardium.

S100A1: a multifaceted therapeutic target in cardiovascular disease.

Cardiovascular disease is the leading cause of death worldwide, showing a dramatically growing prevalence. It is still associated with a poor clinical prognosis, indicating insufficient long-term treatment success of currently available therapeutic strategies. Investigations of the pathomechanisms underlying cardiovascular disorders uncovered the Ca(2+) binding protein S100A1 as a critical regulator of both cardiac performance and vascular biology.

Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes.

Cardiac hypertrophy is an independent risk for heart failure (HF) and sudden death. Deciphering signalling pathways dependent on extracellular calcium (Ca(2+)) influx that control normal and pathological cardiac growth may enable identification of novel therapeutic targets. The objective of the present study is to determine the role of the Ca(2+) release-activated Ca(2+) (CRAC) channel Orai1 and stromal interaction molecule 1 (Stim1) in postnatal cardiomyocyte store operated Ca(2+) entry (SOCE) and impact on normal and hypertrophic postnatal cardiomyocyte growth.

Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension.

Background: In idiopathic pulmonary arterial hypertension (IPAH), peripheral airway obstruction is frequent. This is partially attributed to the mediator dysbalance, particularly an excess of endothelin-1 (ET-1), to increased pulmonary vascular and airway tonus and to local inflammation. Bosentan (ET-1 receptor antagonist) improves pulmonary hemodynamics, exercise limitation, and disease severity in IPAH.

S100A1 in cardiovascular health and disease: closing the gap between basic science and clinical therapy.

Calcium (Ca(2+)) signaling plays a major role in a wide range of physiological functions including control and regulation of cardiac and skeletal muscle performance and vascular tone. As all Ca(2+) signals require proteins to relay intracellular Ca(2+) oscillations downstream to different signaling networks, a specific toolkit of Ca(2+)-sensor proteins involving members of the EF-hand S100 Ca(2+) binding protein superfamily maintains the integrity of the Ca(2+) signaling in a variety of cardiac and vascular cells, transmitting the message with great precision and in a temporally and spatially coordinated manner. Indeed, the possibility that S100 proteins might contribute to heart and vascular diseases was first suggested by the discovery of distinctive patterns of S100 expression in healthy and diseased hearts and vasculature from humans and animal heart failure (HF) models.

Decreased contractility due to energy deprivation in a transgenic rat model of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is associated with cardiac hypertrophy, diastolic dysfunction, and sudden death. Recently, it has been suggested that inefficient energy utilization could be a common molecular pathway of HCM-related mutations. We have previously generated transgenic Sprague-Dawley rats overexpressing a truncated cardiac troponin T (DEL-TNT) molecule, displaying typical features of HCM such as diastolic dysfunction and an increased susceptibility to ventricular arrhythmias.