Signaling effectors underlying pathologic growth and remodeling of the heart

The Journal of clinical investigation (Impact Factor: 13.22). 01/2013; 123(1):37-45. DOI: 10.1172/JCI62839
Source: PubMed


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.

  • Source
    • "In particular, pH is likely to influence the activity of transcription factors such as EGR1 (Early-Growth Response 1), ERα (Estrogen Receptor α), GCR (Glucocorticoid receptor) and NFκB (Nuclear Factor kappa-lightchain-enhancer of activated B-cells) which contain protonatable histidine residues near sites of interaction with DNA [3] [4] [5] [6]. Of relevance to the heart, the DNA-binding motif of NFAT (Nuclear Factor of Activated T-cells), a transcription factor involved in pro-hypertrophic signaling [7] [8], contains conserved histidines residues. Protons can affect cardiac function indirectly by modulating the dynamics of other signaling molecules, such as Ca 2+ ions [9] [10] [11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Biochemical signals acting on the nucleus can regulate gene expression. Despite the inherent affinity of nucleic acids and nuclear proteins (e.g. transcription factors) for protons, little is known about the mechanisms that regulate nuclear pH (pHnuc), and how these could be exploited to control gene expression. Here, we show that pHnuc dynamics can be imaged using the DNA-binding dye Hoechst 33342. Nuclear pores allow the passage of medium-sized molecules (calcein), but protons must first bind to mobile buffers in order to gain access to the nucleoplasm. Fixed buffering residing in the nucleus of permeabilised cells was estimated to be very weak on the basis of the large amplitude of pHnuc transients evoked by photolytic H(+)-uncaging or exposure to weak acids/bases. Consequently, the majority of nuclear pH buffering is sourced from the cytoplasm in the form of mobile buffers. Effective proton diffusion was faster in nucleoplasm than in cytoplasm, in agreement with the higher mobile-to-fixed buffering ratio in the former. Cardiac myocyte pHnuc changed in response to maneuvers that alter nuclear Ca(2+) signals. Blocking Ca(2+) release from inositol-1,4,5-trisphosphate receptors stably alkalinized the nucleus. This Ca(2+)-pH interaction may arise from competitive binding to common chemical moieties. Competitive binding to mobile buffers may couple the efflux of Ca(2+) via nuclear pores with a counterflux of protons. This can generate a stable pH gradient between cytoplasm and nucleus that is sensitive to the state of nuclear Ca(2+) signaling. The unusual behavior of protons in the nucleus provides new mechanisms for regulating cardiac nuclear biology. Copyright © 2015. Published by Elsevier Ltd.
    Preview · Article · Jul 2015 · Journal of Molecular and Cellular Cardiology
  • Source
    • "Characterized by an increase in the size of cardiac myocytes and whole heart enlargement, cardiac hypertrophy is an adaptive reaction in response to increased pressure overload. Sustained after-overload usually induces an initial compensatory hypertrophy, which can progress to pathologic cardiac hypertrophy and finally to congestive heart failure [1]. Overpressure is a major initiative stimulus triggering protein synthesis, gene expression reprogramming, and activation of various signaling molecules, such as protein kinase C (PKC) pathway, the mitogen-activated protein kinases (MAPK) pathway, and the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway, and, thus, subsequently modifies transcriptional regulatory factors (GATA4) and resulting in cardiac hypertrophy [2] [3] [4]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background. Cardiac hypertrophy occurs in many cardiovascular diseases. Apocynum tablet (AT), a traditional Chinese medicine, has been widely used in China to treat patients with hypertension. However, the underlying molecular mechanisms of AT on the hypertension-induced cardiac hypertrophy remain elusive. The current study evaluated the effect and mechanisms of AT on cardiac hypertrophy. Methods. We created a mouse model of cardiac hypertrophy by inducing pressure overload with surgery of transverse aortic constriction (TAC) and then explored the effect of AT on the development of cardiac hypertrophy using 46 mice in 4 study groups (combinations of AT and TAC). In addition, we evaluated the signaling pathway of phosphorylation of ERK1/2, AKT, and protein expression of GATA4 in the cardioprotective effects of AT using Western blot. Results. AT inhibited the phosphorylation of Thr202/Tyr204 sites of ERK1/2, Ser473 site of AKT, and protein expression of GATA4 and significantly inhibited cardiac hypertrophy and cardiac fibrosis at 2 weeks after TAC surgery (P < 0.05). Conclusions. We experimentally demonstrated that AT inhibits cardiac hypertrophy via suppressing phosphorylation of ERK1/2 and AKT.
    Full-text · Article · Jun 2014 · Evidence-based Complementary and Alternative Medicine
  • Source
    • "Following a flurry of investment in previous decades, many pharmacological interventions were met with failure at the stage of progressing into clinical trials, at which point significant investment had already been made and lost. Preclinical testing did not translate into the clinic as expected, and this remains an ongoing problem (Hausenloy & Yellon, 2013; van Berlo et al., 2013). Translational breakthroughs do exist, most notably cyclosporine A infusion for reducing reperfusion injury and SERCA2a gene therapy for restoring pump function in the failing heart. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure is one of the paramount global causes of morbidity and mortality. Despite this pandemic need, the available clinical counter-measures have not altered substantially in recent decades, most notably in the context of pharmacological interventions. Cell death plays a causal role in heart failure, and its inhibition poses a promising approach that has not been thoroughly explored. In previous approaches to target discovery, clinical failures have reflected a deficiency in mechanistic understanding, and in some instances, failure to systematically translate laboratory findings toward the clinic. Here, we review diverse mouse models of heart failure, with an emphasis on those that identify potential targets for pharmacological inhibition of cell death, and on how their translation into effective therapies might be improved in the future.
    Full-text · Article · Jun 2014 · Current Topics in Developmental Biology
Show more

We use cookies to give you the best possible experience on ResearchGate. Read our cookies policy to learn more.