Signaling effectors underlying pathologic growth and remodeling of the heart

Abstract

Cardiovascular disease is the number one cause of mortality in the Western world. The heart responds to many cardiopathological conditions with hypertrophic growth by enlarging individual myocytes to augment cardiac pump function and decrease ventricular wall tension. Initially, such cardiac hypertrophic growth is often compensatory, but as time progresses these changes become maladaptive. Cardiac hypertrophy is the strongest predictor for the development of heart failure, arrhythmia, and sudden death. Here we discuss therapeutic avenues emerging from molecular and genetic studies of cardiovascular disease in animal models. The majority of these are based on intracellular signaling pathways considered central to pathologic cardiac remodeling and hypertrophy, which then leads to heart failure. We focus our discussion on selected therapeutic targets that have more recently emerged and have a tangible translational potential given the available pharmacologic agents that could be readily evaluated in human clinical trials.

Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy

“…The in vivo staining of zebrafish embryos at 2 dpf with MitoSOX Red revealed the presence of high levels of ROS in the hearts of Tom70 morphants compared with MO-ctrl ( Figure 5G). We also measured the expression levels of a regulated set of genes involved in cardiac hypertrophy, including ANP, α-MHC and GATA4 [16,17], in the morphant hearts. As shown in Figure 5H, the inactivation of Tom70 increased the expression of ANP and reduced the expression of α-MHC and GATA4.…”

ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK‐AKT Signaling

“…To elucidate these possible mechanisms, we first investigated the expression and activity of mitogen‐activated protein kinase (MAPK) signaling molecules, as the MAPK pathway is known to play a fundamental role in pathological cardiac hypertrophy 3, 5. Compared with the sham operation, pressure overload by AB operation caused an increase in phosphorylation of MAPK signal pathway members.…”

“…To investigate the molecular mechanism by which ADAM23 mediates its effects on cardiac hypertrophy, we first examined the MAPK signaling pathway, a pivotal role in the development of cardiac hypertrophy 3. Unexpectedly, we found that MAPK activities were affected by neither ADAM23 deficiency nor overexpression, which indicated that the anti‐hypertrophic effects of ADAM23 were independent of MAPK signaling.…”

“…Although cardiac hypertrophy initially might be compensatory and adaptive, prolonged pathological hypertrophy eventually leads to functional and histological deterioration of the myocardium, fibrosis, and altered cardiac gene expression and then congestive heart failure, arrhythmia, and sudden death 1, 3. In fact, clinical and epidemiological studies have identified that cardiac hypertrophy is an important independent risk factor for the development of heart failure and increases the risk of cardiac morbidity and mortality 4.…”

“…In fact, clinical and epidemiological studies have identified that cardiac hypertrophy is an important independent risk factor for the development of heart failure and increases the risk of cardiac morbidity and mortality 4. Multiple signaling pathways that involved in the development of cardiac hypertrophy have been identified, eg, mitogen‐activated protein kinase (MAPK) signaling3, 5 and protein kinase B (AKT) signaling 3, 6. However, the key components that determine the pathogenesis and progression of cardiac hypertrophy remain incompletely understood.…”