The complex interplay between mitochondrial dynamics and cardiac metabolism.

Mitochondria are highly dynamic organelles, capable of undergoing constant fission and fusion events, forming networks. These dynamic events allow the transmission of chemical and physical messengers and the exchange of metabolites within the cell. In this article we review the signaling mechanisms controlling mitochondrial fission and fusion, and its relationship with cell bioenergetics, especially in the heart.

Autophagy in cardiac plasticity and disease.

The heart is a highly plastic organ. In response to the physiological stress of normal life, as well as the pathological stress of disease, the myocardium manifests robust and rapid changes in mass. In the context of disease-associated stress, this myocardial remodeling response can culminate in ventricular thinning, mechanical dysfunction, and a clinical syndrome of heart failure.

Sustained hemodynamic stress disrupts normal circadian rhythms in calcineurin-dependent signaling and protein phosphorylation in the heart.

Rationale: Despite overwhelming evidence of the importance of circadian rhythms in cardiovascular health and disease, little is known regarding the circadian regulation of intracellular signaling pathways controlling cardiac function and remodeling.

Objective: To assess circadian changes in processes dependent on the protein phosphatase calcineurin, relative to changes in phosphorylation of cardiac proteins, in normal, hypertrophic, and failing hearts.

Methods And Results: We found evidence of large circadian oscillations in calcineurin-dependent activities in the left ventricle of healthy C57BL/6 mice.

Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology.

The reductions in mortality and morbidity being achieved among cancer patients with current therapies represent a major achievement. However, given their mechanisms of action, many anti-cancer agents may have significant potential for cardiovascular side effects, including the induction of heart failure. The magnitude of this problem remains unclear and is not readily apparent from current clinical trials of emerging targeted agents, which generally under-represent older patients and those with significant co-morbidities.

A dynamic notch injury response activates epicardium and contributes to fibrosis repair.

Rationale: Transgenic Notch reporter mice express enhanced green fluorescent protein in cells with C-promoter binding factor-1 response element transcriptional activity (CBF1-RE(x)₄-EGFP), providing a unique and powerful tool for identifying and isolating "Notch-activated" progenitors.

Objective: We asked whether, as in other tissues of this mouse, EGFP localized and functionally tagged adult cardiac tissue progenitors, and, if so, whether this cell-based signal could serve as a quantitative and qualitative biosensor of the injury repair response of the heart.

Methods And Results: In addition to scattered endothelial and interstitial cells, Notch-activated (EGFP(+)) cells unexpectedly richly populated the adult epicardium.

Targeting of protein phosphatases PP2A and PP2B to the C-terminus of the L-type calcium channel Ca v1.2.

The L-type Ca(2+) channel Ca(v)1.2 forms macromolecular signaling complexes that comprise the β(2) adrenergic receptor, trimeric G(s) protein, adenylyl cyclase, and cAMP-dependent protein kinase (PKA) for efficient signaling in heart and brain. The protein phosphatases PP2A and PP2B are part of this complex.

Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice.

MicroRNAs inhibit mRNA translation or promote mRNA degradation by binding complementary sequences in 3' untranslated regions of target mRNAs. MicroRNA-21 (miR-21) is upregulated in response to cardiac stress, and its inhibition by a cholesterol-modified antagomir has been reported to prevent cardiac hypertrophy and fibrosis in rodents in response to pressure overload. In contrast, we have shown here that miR-21-null mice are normal and, in response to a variety of cardiac stresses, display cardiac hypertrophy, fibrosis, upregulation of stress-responsive cardiac genes, and loss of cardiac contractility comparable to wild-type littermates.

Spironolactone therapy is associated with reduced ventricular tachycardia rate in patients with cardiomyopathy.

Introduction: Multiple pharmacological therapies currently in prevalent clinical use for cardiac diseases have antifibrotic properties. Spironolactone, a potent antifibrotic agent, is currently used for advanced heart failure. Therapies such as HMG-CoA reductase inhibitors (statins) and angiotensin-converting enzyme inhibitors (ACEi) also have antifibrotic properties.

Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo.

In contrast to studies on skeletal and smooth muscles, the identity of kinases in the heart that are important physiologically for direct phosphorylation of myosin regulatory light chain (RLC) is not known. A Ca(2+)/calmodulin-activated myosin light chain kinase is expressed only in cardiac muscle (cMLCK), similar to the tissue-specific expression of skeletal muscle MLCK and in contrast to the ubiquitous expression of smooth muscle MLCK. We have ablated cMLCK expression in male mice to provide insights into its role in RLC phosphorylation in normally contracting myocardium.

Mitochondrial fission and autophagy in the normal and diseased heart.

Sustained hypertension promotes structural, functional and metabolic remodeling of cardiomyocyte mitochondria. As long-lived, postmitotic cells, cardiomyocytes turn over mitochondria continuously to compensate for changes in energy demands and to remove damaged organelles. This process involves fusion and fission of existing mitochondria to generate new organelles and separate old ones for degradation via autophagy.

Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy.

Since the initial description of the phenomenon by Jennings et al 50 years ago, our understanding of the underlying mechanisms of reperfusion injury has grown significantly. Its pathogenesis reflects the confluence of multiple pathways, including ion channels, reactive oxygen species, inflammation, and endothelial dysfunction. The purposes of this review are to examine the current state of understanding of ischemia-reperfusion injury, as well as to highlight recent interventions aimed at this heretofore elusive target.

FoxO, autophagy, and cardiac remodeling.

In response to changes in workload, the heart grows or shrinks. Indeed, the myocardium is capable of robust and rapid structural remodeling. In the setting of normal, physiological demand, the heart responds with hypertrophic growth of individual cardiac myocytes, a process that serves to maintain cardiac output and minimize wall stress.

Carbamazepine alone and in combination with doxycycline attenuates isoproterenol-induced cardiac hypertrophy.

β-adrenergic signaling is involved in the development of cardiac hypertrophy (CH), justifying the use of β-blockers as a therapy to minimize and postpone the consequences of this disease. Evidence suggests that adenylate cyclase, a downstream effector of the β-adrenergic pathway, might be a therapeutic target. We examined the effects of the anti-epileptic drug carbamazepine (CBZ), an inhibitor of adenylate cyclase.

The CCAAT/enhancer binding protein beta (C/EBPbeta) cooperates with NFAT to control expression of the calcineurin regulatory protein RCAN1-4.

Regulator of calcineurin 1 (RCAN1) inhibits the protein phosphatase calcineurin and is required for appropriate immune responses, synaptic plasticity, vascular tone, angiogenesis, and cardiac remodeling. Expression of the RCAN1-4 isoform is under the control of the calcineurin-responsive transcription factor NFAT. Typically, NFATs act in cooperation with other transcription factors to achieve maximal activation of gene expression.

Diminished cardiac fibrosis in heart failure is associated with altered ventricular arrhythmia phenotype.

Objectives: We sought to define the role of interstitial fibrosis in the proarrhythmic phenotype of failing ventricular myocardium.

Background: Multiple cellular events that occur during pathological remodeling of the failing ventricle are implicated in the genesis of ventricular tachycardia (VT), including interstitial fibrosis. Recent studies suggest that ventricular fibrosis is reversible, and current anti-remodeling therapies attenuate ventricular fibrosis.

Autophagy in hypertensive heart disease.

In response to hypertension, the heart manifests robust hypertrophic growth, which offsets load-induced elevations in wall stress. If sustained, this hypertrophic response is a major risk factor for systolic dysfunction and heart failure. Extensive research efforts have focused on the progression from hypertrophy to failure; however, precise understanding of underlying mechanisms remains elusive.

Electrophysiological remodeling in heart failure.

Heart failure affects nearly 6 million Americans, with a half-million new cases emerging each year. Whereas up to 50% of heart failure patients die of arrhythmia, the diverse mechanisms underlying heart failure-associated arrhythmia are poorly understood. As a consequence, effectiveness of antiarrhythmic pharmacotherapy remains elusive.

Cardiomyocyte autophagy: remodeling, repairing, and reconstructing the heart.

Autophagy is an evolutionarily conserved catabolic pathway of lysosome-dependent turnover of damaged proteins and organelles. When nutrients are in short supply, bulk removal of cytoplasmic components by autophagy replenishes depleted energy stores, a process critical for maintaining cellular homeostasis. However, prolonged activation of autophagic pathways can result in cell death.

Myocyte enhancer factor 2 and class II histone deacetylases control a gender-specific pathway of cardioprotection mediated by the estrogen receptor.

Rationale: Gender differences in cardiovascular disease have long been recognized and attributed to beneficial cardiovascular actions of estrogen. Class II histone deacetylases (HDACs) act as key modulators of heart disease by repressing the activity of the myocyte enhancer factor (MEF)2 transcription factor, which promotes pathological cardiac remodeling in response to stress. Although it is proposed that HDACs additionally influence nuclear receptor signaling, the effect of class II HDACs on gender differences in cardiovascular disease remains unstudied.

Cx30.2 enhancer analysis identifies Gata4 as a novel regulator of atrioventricular delay.

The cardiac conduction system comprises a specialized tract of electrically coupled cardiomyocytes responsible for impulse propagation through the heart. Abnormalities in cardiac conduction are responsible for numerous forms of cardiac arrhythmias, but relatively little is known about the gene regulatory mechanisms that control the formation of the conduction system. We demonstrate that a distal enhancer for the connexin 30.

Hic-5 is required for fetal gene expression and cytoskeletal organization of neonatal cardiac myocytes.

Cardiac costameres link the extracellular matrix to the sarcomere at the z-disc and contain proteins such as integrins and other signaling molecules implicated in the regulation of pathological hypertrophy. Paxillin family members, hic-5 and paxillin, are scaffolding proteins associated with the integrin complex that have been shown to mediate numerous protein interactions in other cell types. While paxillin has been described in postnatal heart, hic-5 has not been identified.

Physical and functional interaction between calcineurin and the cardiac L-type Ca2+ channel.

The L-type Ca(2+) channel (LTCC) is the major mediator of Ca(2+) influx in cardiomyocytes, leading to both mechanical contraction and activation of signaling cascades. Among these Ca(2+)-activated cascades is calcineurin, a protein phosphatase that promotes hypertrophic growth of the heart. Coimmunoprecipitations from heart extracts and pulldowns using heterologously expressed proteins provided evidence for direct binding of calcineurin at both the N and C termini of alpha(1)1.

Autophagy in load-induced heart disease.

The heart is a highly plastic organ capable of remodeling in response to changes in physiological or pathological demand. When workload increases, the heart compensates through hypertrophic growth of individual cardiomyocytes to increase cardiac output. However, sustained stress, such as occurs with hypertension or following myocardial infarction, triggers changes in sarcomeric protein composition and energy metabolism, loss of cardiomyocytes, ventricular dilation, reduced pump function, and ultimately heart failure.