J. Cardiovasc. Dev. Dis.2014, 1(1), 134-145; doi:10.3390/jcdd1010134 - published online 22 May 2014 Show/Hide Abstract
Abstract: Congenital heart disease (CHD) affects the intricate structure and function of the heart and is one of the leading causes of death in newborns. The genetic basis of CHD is beginning to emerge. Our laboratory has been engaged in identifying mutations in genes linked to CHD both in families and in sporadic cases. Over the last two decades, we have employed linkage analysis, targeted gene sequencing and genome wide association studies to identify genes involved in CHDs. Cardiac specific genes that encode transcription factors and sarcomeric proteins have been identified and linked to CHD. Functional analysis of the relevant mutant proteins has established the molecular mechanisms of CHDs in our studies.
J. Cardiovasc. Dev. Dis.2014, 1(1), 121-133; doi:10.3390/jcdd1010121 - published online 21 May 2014 Show/Hide Abstract
Abstract: 3'-5'-cyclic adenosine monophosphate (cAMP) is a second messenger, which plays an important role in the heart. It is generated in response to activation of G-protein-coupled receptors (GPCRs). Initially, it was thought that protein kinase A (PKA) exclusively mediates cAMP-induced cellular responses such as an increase in cardiac contractility, relaxation, and heart rate. With the identification of the exchange factor directly activated by cAMP (EPAC) and hyperpolarizing cyclic nucleotide-gated (HCN) channels as cAMP effector proteins it became clear that a protein network is involved in cAMP signaling. The Popeye domain containing (Popdc) genes encode yet another family of cAMP-binding proteins, which are prominently expressed in the heart. Loss-of-function mutations in mice are associated with cardiac arrhythmia and impaired skeletal muscle regeneration. Interestingly, the cardiac phenotype, which is present in both, Popdc1 and Popdc2 null mutants, is characterized by a stress-induced sinus bradycardia, suggesting that Popdc proteins participate in cAMP signaling in the sinuatrial node. The identification of the two-pore channel TREK-1 and Caveolin 3 as Popdc-interacting proteins represents a first step into understanding the mechanisms of heart rate modulation triggered by Popdc proteins.
J. Cardiovasc. Dev. Dis.2014, 1(1), 111-120; doi:10.3390/jcdd1010111 - published online 21 May 2014 Show/Hide Abstract
Abstract: The coxsackievirus and adenovirus receptor (CAR, CXADR) is a multi-functional cell adhesion molecule which forms with CLMP, BT-IgSF, ESAM and CTX a structural subgroup within the Ig superfamily. These proteins share an overall domain organization with two extracellular Ig domains, a transmembrane region and a cytoplasmic tail which includes a PDZ binding motif. CAR is strongly expressed in brain and heart during embryonic development and becomes down-regulated in early postnatal stages. Cell adhesion experiments, binding studies and as well as crystallographic investigations on the extracellular domain reveal a flexible ectodomain for CAR that mediates homophilic and heterophilic binding. Several animal models showed an essential role for CAR during embryonic heart development and for electrical conduction between neighboring cardiomyocytes at mature stages. CAR gets re-expressed in diseased or damaged cardiac tissue, probably to induce regeneration and remodeling of the cardiac muscle.
J. Cardiovasc. Dev. Dis.2014, 1(1), 98-110; doi:10.3390/jcdd1010098 - published online 21 May 2014 Show/Hide Abstract
Abstract: Active Wnt/β-catenin signaling is essential for proper cardiac specification, progenitor expansion and myocardial growth. During development, the mass of the embryonic heart increases multiple times to achieve the dimensions of adult ventricular chambers. Cell division in the embryonic heart is fairly present, whereas cell turnover in the adult myocardium is extremely low. Understanding of embryonic cardiomyocyte cell-replication, therefore, could improve strategies for cardiac regenerative therapeutics. Here, we review which role Wnt signaling plays in cardiac development and highlight a selection of attempts that have been made to modulate Wnt signaling after cardiac ischemic injury to improve cardiac function and reduce infarct size.
J. Cardiovasc. Dev. Dis.2014, 1(1), 83-97; doi:10.3390/jcdd1010083 - published online 21 May 2014 Show/Hide Abstract
Abstract: In the last four decades, enormous progress has been made in the treatment of congenital heart diseases (CHD); most patients now survive into adulthood, albeit with residual lesions. As a consequence, the focus has shifted from initial treatment to long-term morbidity and mortality. An important predictor for long-term outcome is right ventricular (RV) dysfunction, but knowledge on the mechanisms of RV adaptation and dysfunction is still scarce. This review will summarize the main features of RV adaptation to CHD, focusing on recent knowledge obtained in experimental models of the most prevalent abnormal loading conditions, i.e., pressure load and volume load. Models of increased pressure load for the RV have shown a similar pattern of responses, i.e., increased contractility, RV dilatation and hypertrophy. Evidence is accumulating that RV failure in response to increased pressure load is marked by progressive diastolic dysfunction. The mechanisms of this progressive dysfunction are insufficiently known. The RV response to pressure load shares similarities with that of the LV, but also has specific features, e.g., capillary rarefaction, oxidative stress and inflammation. The contribution of these pathways to the development of failure needs further exploration. The RV adaptation to increased volume load is an understudied area, but becomes increasingly important in the growing groups of survivors of CHD, especially with tetralogy of Fallot. Recently developed animal models may add to the investigation of the mechanisms of RV adaptation and failure, leading to the development of new RV-specific therapies.
J. Cardiovasc. Dev. Dis.2014, 1(1), 73-82; doi:10.3390/jcdd1010073 - published online 10 April 2014 Show/Hide Abstract
Abstract: Cardiac regeneration remains a clinical target regardless of numerous therapeutic concepts. We formulated a hypothesis claiming that periodic coronary venous pressure elevation (PICSO; Pressure controlled Intermittent Coronary Sinus Occlusion) initiates embedded, but dormant developmental processes in adult jeopardized hearts. Hemodynamics in the primitive beating heart tube is sensed transducing “mechanical” epigenetic information during normal cardiac development. In analogy mechanotransduction via shear stress and pulsatile stretch induced by periodic elevation of blood pressure in cardiac veins reconnects this dormant developmental signal, setting regenerative impulses in the adult heart. Significant increase of hemeoxygenase-1 gene expression (p < 0.001) and vascular endothelial growth factor (VEGF) (p < 0.002) as well as production of VEGRF2 in experimental infarction underscores the resurgence of developmental stimuli by PICSO. Molecular findings correspond with risk reduction (p < 0.0001) in patients with acute coronary syndromes as well as observations in heart failure patients showing substantial risk reduction up to 5 years endorsing our hypothesis and preclinical experience that PICSO via hemodynamic power activates regenerative processes also in adult human hearts. These results emphasize that our proposed hypothesis “embryonic recall” claiming revival of an imbedded albeit dormant “epigenetic” process is able not only to sculpture myocardium in the embryo, but also to redesign structure in the adult and failing heart.