Ca
            <sup>2+</sup>
            Cycling and New Therapeutic Approaches for Heart Failure

Lompré, Anne‐Marie; Hajjar, Roger J.; Harding, Siân E.; Kranias, Evangelia G.; Lohse, Martin J.; Marks, Andrew R.

doi:10.1161/circulationaha.109.890954

Cited by 116 publications

(103 citation statements)

References 136 publications

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“…33,34 FGF9 antagonized these structural and molecular features of pathological hypertrophy. Notably, FGF9 enhanced systolic function and reduced heart failure mortality after MI, thus clearly establishing that expression of FGF9 in the adult mouse myocardium is beneficial during recovery from an acute MI.…”

Section: Korf-klingebiel Et Al Fgf9 Improves Outcome After MI 511mentioning

confidence: 93%

Conditional Transgenic Expression of Fibroblast Growth Factor 9 in the Adult Mouse Heart Reduces Heart Failure Mortality After Myocardial Infarction

et al. 2011

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Background-Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. Methods and Results-We used a tetracycline-responsive binary transgene system based on the ␣-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice. Conclusions-Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI. (Circulation. 2011;123:504-514.)Key Words: angiogenesis Ⅲ cardiac remodeling Ⅲ FGF9 Ⅲ mortality Ⅲ myocardial infarction A dvances in treatment have resulted in declining mortality rates after acute myocardial infarction (MI). Unfortunately, the decrease in postinfarct mortality is paralleled by an increase in the incidence of heart failure in patients surviving with significant residual myocardial damage. 1 Loss of contractile tissue after MI induces profound alterations of left ventricular (LV) tissue architecture that are characterized by chamber dilatation and pathological hypertrophy of the noninfarcted myocardium, leading to contractile dysfunction and reduced long-term survival. 2 Clinical Perspective on p 514During midgestational heart development, the heart undergoes a dramatic increase in size that is attributable to cardiomyoblast proliferation and the concurrent formation of the coronary vascular system. 3,4 LV contractile function increases during this period of rapid cardiac growth, 5 thus providing an example that cardiac mass and size can increase conside...

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Section: Korf-klingebiel Et Al Fgf9 Improves Outcome After MI 511mentioning

confidence: 93%

Conditional Transgenic Expression of Fibroblast Growth Factor 9 in the Adult Mouse Heart Reduces Heart Failure Mortality After Myocardial Infarction

et al. 2011

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“…However, patients with an ATP2A2 mutation and haploinsufficiency (Darier disease) do not have cardiac dysfunction (49). Nevertheless, restoration of normal levels of SERCA2a has been targeted as a novel therapeutic for HF (4). Phospholamban controls the affinity of SERCA2 for Ca 2+ .…”

Section: Figurementioning

confidence: 99%

Calcium cycling proteins and heart failure: mechanisms and therapeutics

Marks¹

2013

J. Clin. Invest.

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322

290

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Ca 2+ -dependent signaling is highly regulated in cardiomyocytes and determines the force of cardiac muscle contraction. Ca 2+ cycling refers to the release and reuptake of intracellular Ca 2+ that drives muscle contraction and relaxation. In failing hearts, Ca 2+ cycling is profoundly altered, resulting in impaired contractility and fatal cardiac arrhythmias. The key defects in Ca 2+ cycling occur at the level of the sarcoplasmic reticulum (SR), a Ca 2+ storage organelle in muscle. Defects in the regulation of Ca 2+ cycling proteins including the ryanodine receptor 2, cardiac (RyR2)/ Ca 2+ release channel macromolecular complexes and the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a)/phospholamban complex contribute to heart failure. RyR2s are oxidized, nitrosylated, and PKA hyperphosphorylated, resulting in "leaky" channels in failing hearts. These leaky RyR2s contribute to depletion of Ca 2+ from the SR, and the leaking Ca 2+ depolarizes cardiomyocytes and triggers fatal arrhythmias. SERCA2a is downregulated and phospholamban is hypophosphorylated in failing hearts, resulting in impaired SR Ca 2+ reuptake that conspires with leaky RyR2 to deplete SR Ca 2+ . Two new therapeutic strategies for heart failure (HF) are now being tested in clinical trials: (a) fixing the leak in RyR2 channels with a novel class of Ca 2+ -release channel stabilizers called Rycals and (b) increasing expression of SERCA2a to improve SR Ca 2+ reuptake with viral-mediated gene therapy. There are many potential opportunities for additional mechanism-based therapeutics involving the machinery that regulates Ca 2+ cycling in the heart. Excitation-contraction couplingWith each beat of the heart, Ca 2+ is released from the sarcoplasmic reticulum (SR) via the ryanodine receptor 2, cardiac (RyR2), raising the cytosolic Ca 2+ concentration about ten-fold (∼1 μM) and activating cardiac muscle contraction (Figure 1). The Ca 2+ is then pumped back into the SR by the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a), lowering the cytosolic Ca 2+ concentration to baseline levels (∼100 nM) and causing relaxation. The Ca 2+ release and reuptake cycle is initiated by the action potential, an electrical signal that depolarizes the plasma membrane and the specialized invagination called the transverse tubule (T tubule). Voltage-gated Ca 2+ channels on the T tubule are activated by depolarization and allow a small amount of Ca 2+ to run down its concentration gradient from mM external Ca 2+ concentration to nM internal Ca 2+ concentration. This entering Ca 2+ binds to and activates RyR2 channels, which release Ca 2+ stored at high concentration (in the millimolar range) in the SR. The Ca 2+ binds to troponin C, allowing actin-myosin cross-bridging and the thick and thin filaments of the sarcomere to slide past each other, shortening the sarcomere and causing cardiac muscle contraction. Heart failureHeart failure (HF) is the leading cause of mortality and morbidity in developed countries. The incidence of HF continues to increase a...

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“…This enables the specificity of each cAMP response associated with local pools of PKA responsible for phosphorylation of particular downstream effectors. In cardiomyocytes (CMs), the existence of several cAMP microdomains has been proposed, which are located, for example, around calcium-handling proteins 1,13 . Although several localized cAMP biosensors have been developed and used in transfected cell lines or neonatal cardiac cells 14 , it is unclear whether such targeted biosensors can be successfully used in vivo.…”

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confidence: 99%

In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease

et al. 2015

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3 0 ,5 0 -cyclic adenosine monophosphate (cAMP) is an ubiquitous second messenger that regulates physiological functions by acting in distinct subcellular microdomains. Although several targeted cAMP biosensors are developed and used in single cells, it is unclear whether such biosensors can be successfully applied in vivo, especially in the context of disease. Here, we describe a transgenic mouse model expressing a targeted cAMP sensor and analyse microdomain-specific second messenger dynamics in the vicinity of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). We demonstrate the biocompatibility of this targeted sensor and its potential for real-time monitoring of compartmentalized cAMP signalling in adult cardiomyocytes isolated from a healthy mouse heart and from an in vivo cardiac disease model. In particular, we uncover the existence of a phosphodiesterase-dependent receptor-microdomain communication, which is affected in hypertrophy, resulting in reduced b-adrenergic receptor-cAMP signalling to SERCA.

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Ca ²⁺ Cycling and New Therapeutic Approaches for Heart Failure

Cited by 116 publications

References 136 publications

Conditional Transgenic Expression of Fibroblast Growth Factor 9 in the Adult Mouse Heart Reduces Heart Failure Mortality After Myocardial Infarction

Conditional Transgenic Expression of Fibroblast Growth Factor 9 in the Adult Mouse Heart Reduces Heart Failure Mortality After Myocardial Infarction

Calcium cycling proteins and heart failure: mechanisms and therapeutics

In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease

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Ca 2+ Cycling and New Therapeutic Approaches for Heart Failure

Cited by 116 publications

References 136 publications

Conditional Transgenic Expression of Fibroblast Growth Factor 9 in the Adult Mouse Heart Reduces Heart Failure Mortality After Myocardial Infarction

Conditional Transgenic Expression of Fibroblast Growth Factor 9 in the Adult Mouse Heart Reduces Heart Failure Mortality After Myocardial Infarction

Calcium cycling proteins and heart failure: mechanisms and therapeutics

In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease

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Ca ²⁺ Cycling and New Therapeutic Approaches for Heart Failure