Essential Role of the RIα Subunit of cAMP-Dependent Protein Kinase in Regulating Cardiac Contractility and Heart Failure Development.

Background: The heart expresses 2 main subtypes of cAMP-dependent protein kinase (PKA; type I and II) that differ in their regulatory subunits, RIα and RIIα. Embryonic lethality of RIα knockout mice limits the current understanding of type I PKA function in the myocardium. The objective of this study was to test the role of RIα in adult heart contractility and pathological remodeling.

STIM2 variants regulate Orai1/TRPC1/TRPC4-mediated store-operated Ca entry and mitochondrial Ca homeostasis in cardiomyocytes.

The stromal interaction molecules (STIMs) are the sarcoplasmic reticulum (SR) Ca sensors that trigger store-operated Ca entry (SOCE) in a variety of cell types. While STIM1 isoform has been the focus of the research in cardiac pathophysiology, the function of the homolog STIM2 remains unknown. Using Ca imaging and patch-clamp techniques, we showed that knockdown (KD) of STIM2 by siRNAs increased SOCE and the I current in neonatal rat ventricular cardiomyocytes (NRVMs).

Circadian regulation of Ca 1.2 expression by RORα in the mouse heart.

Background: In addition to show autonomous beating rhythmicity, the physiological functions of the heart present daily periodic oscillations. Notably the ventricular repolarization itself varies throughout the circadian cycle which was mainly related to the periodic expression of K channels. However, the involvement of the L-type Ca channel (Ca 1.

Dual effect of cardiac FKBP12.6 overexpression on excitation-contraction coupling and the incidence of ventricular arrhythmia depending on its expression level.

FKBP12.6, a binding protein to the immunosuppressant FK506, which also binds the ryanodine receptor (RyR2) in the heart, has been proposed to regulate RyR2 function and to have antiarrhythmic properties. However, the level of FKBP12.

EPAC1 inhibition protects the heart from doxorubicin-induced toxicity.

Anthracyclines, such as doxorubicin (Dox), are widely used chemotherapeutic agents for the treatment of solid tumors and hematologic malignancies. However, they frequently induce cardiotoxicity leading to dilated cardiomyopathy and heart failure. This study sought to investigate the role of the exchange protein directly activated by cAMP (EPAC) in Dox-induced cardiotoxicity and the potential cardioprotective effects of EPAC inhibition.

The SOCE Machinery: An Unbalanced Knowledge between Left and Right Ventricular Pathophysiology.

Right ventricular failure (RVF) is the most important prognostic factor for morbidity and mortality in pulmonary arterial hypertension (PAH) or pulmonary hypertension (PH) caused by left heart diseases. However, right ventricle (RV) remodeling is understudied and not targeted by specific therapies. This can be partly explained by the lack of basic knowledge of RV remodeling.

Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca) signaling contributes to abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration, and arterial contractility. Store-operated Ca entry is involved in Ca homeostasis in PASMCs, but its properties in PAH are unclear.

Housekeeping Proteins Exhibit a High Level of Expression Variability Within Control Group and Between Ischemic Human Heart Biopsies.

Background Human cardiac biopsies are widely used in clinical and fundamental research to decipher molecular events that characterize cardiac physiological and pathophysiological states. One of the main approaches relies on the analysis of semiquantitative immunoblots that reveals alterations in protein expression levels occurring in diseased hearts. To maintain semiquantitative results, expression level of target proteins must be standardized.

Heart failure in mice induces a dysfunction of the sinus node associated with reduced CaMKII signaling.

Dysfunction of the sinoatrial node (SAN), the natural heart pacemaker, is common in heart failure (HF) patients. SAN spontaneous activity relies on various ion currents in the plasma membrane (voltage clock), but intracellular Ca2+ ([Ca2+]i) release via ryanodine receptor 2 (RYR2; Ca2+ clock) plays an important synergetic role. Whereas remodeling of voltage-clock components has been revealed in HF, less is known about possible alterations to the Ca2+ clock.

Aldosterone-Induced Sarco/Endoplasmic Reticulum Ca Pump Upregulation Counterbalances Ca1.2-Mediated Ca Influx in Mesenteric Arteries.

In mesenteric arteries (MAs), aldosterone (ALDO) binds to the endogenous mineralocorticoid receptor (MR) and increases the expression of the voltage-gated L-type Ca1.2 channel, an essential ion channel for vascular contraction, sarcoplasmic reticulum (SR) Ca store refilling, and Ca spark generation. In mesenteric artery smooth muscle cells (MASMCs), Ca influx through Ca1.

Mosaic theory revised: inflammation and salt play central roles in arterial hypertension.

The mosaic theory of hypertension was advocated by Irvine Page ~80 years ago and suggested that hypertension resulted from the close interactions of different causes. Increasing evidence indicates that hypertension and hypertensive end-organ damage are not only mediated by the proposed mechanisms that result in hemodynamic injury. Inflammation plays an important role in the pathophysiology and contributes to the deleterious consequences of arterial hypertension.

RyR2 and Calcium Release in Heart Failure.

Heart Failure (HF) is defined as the inability of the heart to efficiently pump out enough blood to maintain the body's needs, first at exercise and then also at rest. Alterations in Ca handling contributes to the diminished contraction and relaxation of the failing heart. While most Ca handling protein expression and/or function has been shown to be altered in many models of experimental HF, in this review, we focus in the sarcoplasmic reticulum (SR) Ca release channel, the type 2 ryanodine receptor (RyR2).

The role of hyperglycaemia in the development of diabetic cardiomyopathy.

Diabetes mellitus is a metabolic disorder with a chronic hyperglycaemic state. Cardiovascular diseases are the primary cause of mortality in patients with diabetes. Increasing evidence supports the existence of diabetic cardiomyopathy, a cardiac dysfunction with impaired cardiac contraction and relaxation, independent of coronary and/or valvular complications.

Impaired Binding to Junctophilin-2 and Nanostructural Alteration in CPVT Mutation.

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Targeting Orai1-Mediated Store-Operated Ca Entry in Heart Failure.

The archetypal store-operated Ca channels (SOCs), Orai1, which are stimulated by the endo/sarcoplasmic reticulum (ER/SR) Ca sensor stromal interaction molecule 1 (STIM1) upon Ca store depletion is traditionally viewed as instrumental for the function of non-excitable cells. In the recent years, expression and function of Orai1 have gained recognition in excitable cardiomyocytes, albeit controversial. Even if its cardiac physiological role in adult is still elusive and needs to be clarified, Orai1 contribution in cardiac diseases such as cardiac hypertrophy and heart failure (HF) is increasingly recognized.

Activation of sarcolipin expression and altered calcium cycling in cardiomyopathy.

Cardiomyopathy caused by A-type lamins gene () mutations ( cardiomyopathy) is associated with dysfunction of the heart, often leading to heart failure. cardiomyopathy is highly penetrant with bad prognosis with no specific therapy available. Searching for alternative ways to halt the progression of cardiomyopathy, we studied the role of calcium homeostasis in the evolution of this disease.

Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca Handling After Pressure Overload.

Background: Orai1 is a critical ion channel subunit, best recognized as a mediator of store-operated Ca entry (SOCE) in nonexcitable cells. SOCE has recently emerged as a key contributor of cardiac hypertrophy and heart failure but the relevance of Orai1 is still unclear.

Methods: To test the role of these Orai1 channels in the cardiac pathophysiology, a transgenic mouse was generated with cardiomyocyte-specific expression of an ion pore-disruptive Orai1 mutant (C-dnO1).

Specific Upregulation of TRPC1 and TRPC5 Channels by Mineralocorticoid Pathway in Adult Rat Ventricular Cardiomyocytes.

Whereas cardiac TRPC (transient receptor potential canonical) channels and the associated store-operated Ca entry (SOCE) are abnormally elevated during cardiac hypertrophy and heart failure, the mechanism of this upregulation is not fully elucidated but might be related to the activation of the mineralocorticoid pathway. Using a combination of biochemical, Ca imaging, and electrophysiological techniques, we determined the effect of 24-h aldosterone treatment on the TRPCs/Orai-dependent SOCE in adult rat ventricular cardiomyocytes (ARVMs). The 24-h aldosterone treatment (from 100 nM to 1 µM) enhanced depletion-induced Ca entry in ARVMs, as assessed by a faster reduction of Fura-2 fluorescence decay upon the addition of Mn and increased Fluo-4/AM fluorescence following Ca store depletion.

Progression of excitation-contraction coupling defects in doxorubicin cardiotoxicity.

Cardiac failure is a common complication in cancer survivors treated with anthracyclines. Here we followed up cardiac function and excitation-contraction (EC) coupling in an in vivo doxorubicin (Dox) treated mice model (iv, total dose of 10 mg/Kg divided once every three days). Cardiac function was evaluated by echocardiography at 2, 6 and 15 weeks after the last injection.

Arrhythmias precede cardiomyopathy and remodeling of Ca handling proteins in a novel model of long QT syndrome.

Aim: Deletion of QKP1507-1509 amino-acids in SCN5A gene product, the voltage-gated Na channel Nav1.5, has been associated with a large phenotypic spectrum of type 3 long QT syndrome, conduction disorder, dilated cardiomyopathy and high incidence of sudden death. The aim of this study was to develop and characterize a novel model of type 3 long QT syndrome to study the consequences of the QKP1507-1509 deletion.