scholarly journals Sympathetic Stimulation Upregulates the Ca2+ Channel Subunit, CaVα2δ1, via the β1 and ERK 1/2 Pathway in Neonatal Ventricular Cardiomyocytes

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 188
Author(s):  
Aya Al Katat ◽  
Juan Zhao ◽  
Angelino Calderone ◽  
Lucie Parent
Keyword(s):  
Adrenergic Receptor ◽  
Calcium Influx ◽  
Confocal Imaging ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Peak Current Density ◽  
Hypertrophic Response ◽  
Protein Levels ◽  
Ventricular Cardiomyocytes ◽  
Pre Treatment

Intracellular Ca2+ overload secondary to chronic hemodynamic stimuli promotes the recruitment of Ca2+-dependent signaling implicated in cardiomyocyte hypertrophy. The present study tested the hypothesis that sympathetic-mediated hypertrophy of neonatal rat ventricular cardiomyocytes (NRVMs) translated to an increase in calcium influx secondary to the upregulation of CaV1.2 channel subunits. Confocal imaging of norepinephrine (NE)-treated NRVMs revealed a hypertrophic response compared to untreated NRVMs. L-type CaV1.2 peak current density was increased 4-fold following a 24-h stimulation with NE. NE-treated NRVMs exhibited a significant upregulation of CaVα2δ1 and CaVβ3 protein levels without significant changes of CaVα1C and CaVβ2 protein levels. Pre-treatment with the β1-blocker metoprolol failed to inhibit hypertrophy or CaVβ3 upregulation whereas CaVα2δ1 protein levels were significantly reduced. NE promoted the phosphorylation of ERK 1/2, and the response was attenuated by the β1-blocker. U0126 pre-treatment suppressed NE-induced ERK1/2 phosphorylation but failed to attenuate hypertrophy. U0126 inhibition of ERK1/2 phosphorylation prevented NE-mediated upregulation of CaVα2δ1, whereas CaVβ3 protein levels remained elevated. Thus, β1-adrenergic receptor-mediated recruitment of the ERK1/2 plays a seminal role in the upregulation of CaVα2δ1 in NRVMs independent of the concomitant hypertrophic response. However, the upregulation of CaVβ3 protein levels may be directly dependent on the hypertrophic response of NRVMs.

Abstract 3660: Cardioprotective Effect of Eicosapentaenoic Acid, an Important Fish Oil, through Suppression of Endothelin-1-induced Cardiomyocyte Hypertrophy via PPAR-α

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Nobutake Shimojo ◽  
Subrina Jesmin ◽  
Masaaki Soma ◽  
Seiji Maeda ◽  
Takashi Miyauchi ◽  
...  
Keyword(s):  
Eicosapentaenoic Acid ◽  
Fish Oil ◽  
Fold Increase ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Pre Treatment ◽  
Cardiovascular Benefit ◽  
Hypertrophic Changes

A growing body of evidences report the cardiovascular benefit of fish oil including eicosapentaenoic acid (EPA) in humans and experimental animals. While many studies link EPA to cardiac protection, the effect of EPA on endothelin (ET)-1-induced cardiomyocyte hypertrophy is unknown. On the other hand, the previous study demonstrated peroxisomal proliferator-activated receptor (PPAR) -α ligand (fenofibrate) prevents ET-1-induced cardiomyocyte hypertrophy. Though EPA is one of the lignads of PPAR-α, there was no study linking relationship between EPA and PPAR-α on hypertrophied cadiomyocyte. The present study investigated whether ET-1-induced cardiomyocyte hypertrophy could be prevented by the pre-treatment of EPA. Cardiomyocytes were accumulated from neonatal rat heart, cultured and at day 4 of culture, the cardiomyocytes were divided into three groups: control, ET-1 (0.1nM) treated and EPA-pre-treated (10μM) ET-1 groups. A 90% increase in cardiomyocyte surface area, a 75% increase in protein synthesis rate and an elevated actinin expression in cardiomyocyte were observed after ET-1 administration and these changes were greatly prevented by EPA pre-treatment. ET-1-induced hypertrophied cardiomyocytes showed a 2.3-fold and 2.1-fold increase in ANP and BNP mRNA expression, respectively, which were also suppressed by EPA pre-treatment. Pre-treatment of EPA could also attenuate phosphorylated JNK (an important component of MAPK cascade), c-Jun and PPAR-α in ET-1-induced hypertrophied cardiomyocytes. In conclusion, the present study showed that ET-1 can induce significant hypertrophic changes in cardiomyocytes with upregulation of important hypertrophic markers, and that this remodeling was effectively prevented by the pre-administration of EPA through suppressing PPAR-α, phosporylated JNK, and c-Jun.

scholarly journals Lycopene Inhibits Urotensin-II-Induced Cardiomyocyte Hypertrophy in Neonatal Rat Cardiomyocytes

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Hung-Hsing Chao ◽  
Li-Chin Sung ◽  
Cheng-Hsien Chen ◽  
Ju-Chi Liu ◽  
Jin-Jer Chen ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Activity Level ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Urotensin Ii ◽  
Rat Cardiomyocytes ◽  
Protein Levels ◽  
Neonatal Rat Cardiomyocytes ◽  
Tensin Homolog

This study investigated how lycopene affected urotensin-II- (U-II-) induced cardiomyocyte hypertrophy and the possible implicated mechanisms. Neonatal rat cardiomyocytes were exposed to U-II (1 nM) either exclusively or following 6 h of lycopene pretreatment (1–10 μM). The lycopene (3–10 μM) pretreatment significantly inhibited the U-II-induced cardiomyocyte hypertrophy, decreased the production of U-II-induced reactive oxygen species (ROS), and reduced the level of NAD(P)H oxidase-4 expression. Lycopene further inhibited the U-II-induced phosphorylation of the redox-sensitive extracellular signal-regulated kinases. Moreover, lycopene treatment prevented the increase in the phosphorylation of serine-threonine kinase Akt and glycogen synthase kinase-3beta (GSK-3β) caused by U-II without affecting the protein levels of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN). However, lycopene increased the PTEN activity level, suggesting that lycopene prevents ROS-induced PTEN inactivation. These findings imply that lycopene yields antihypertrophic effects that can prevent the activation of the Akt/GSK-3βhypertrophic pathway by modulating PTEN inactivation through U-II treatment. Thus, the data indicate that lycopene prevented U-II-induced cardiomyocyte hypertrophy through a mechanism involving the inhibition of redox signaling. These findings provide novel data regarding the molecular mechanisms by which lycopene regulates cardiomyocyte hypertrophy.

Loss of mitochondrial exo/endonuclease EXOG affects mitochondrial respiration and induces ROS-mediated cardiomyocyte hypertrophy

2015 ◽  
Vol 308 (2) ◽  
pp. C155-C163 ◽  
Author(s):  
Wardit Tigchelaar ◽  
Hongjuan Yu ◽  
Anne Margreet de Jong ◽  
Wiek H. van Gilst ◽  
Pim van der Harst ◽  
...  
Keyword(s):  
Mitochondrial Dna ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Fold Increase ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Dna Integrity ◽  
Hypertrophic Response ◽  
Mitochondrial Ros ◽  
Mitochondrial Dna Repair

Recently, a locus at the mitochondrial exo/endonuclease EXOG gene, which has been implicated in mitochondrial DNA repair, was associated with cardiac function. The function of EXOG in cardiomyocytes is still elusive. Here we investigated the role of EXOG in mitochondrial function and hypertrophy in cardiomyocytes. Depletion of EXOG in primary neonatal rat ventricular cardiomyocytes (NRVCs) induced a marked increase in cardiomyocyte hypertrophy. Depletion of EXOG, however, did not result in loss of mitochondrial DNA integrity. Although EXOG depletion did not induce fetal gene expression and common hypertrophy pathways were not activated, a clear increase in ribosomal S6 phosphorylation was observed, which readily explains increased protein synthesis. With the use of a Seahorse flux analyzer, it was shown that the mitochondrial oxidative consumption rate (OCR) was increased 2.4-fold in EXOG-depleted NRVCs. Moreover, ATP-linked OCR was 5.2-fold higher. This increase was not explained by mitochondrial biogenesis or alterations in mitochondrial membrane potential. Western blotting confirmed normal levels of the oxidative phosphorylation (OXPHOS) complexes. The increased OCR was accompanied by a 5.4-fold increase in mitochondrial ROS levels. These increased ROS levels could be normalized with specific mitochondrial ROS scavengers (MitoTEMPO, mnSOD). Remarkably, scavenging of excess ROS strongly attenuated the hypertrophic response. In conclusion, loss of EXOG affects normal mitochondrial function resulting in increased mitochondrial respiration, excess ROS production, and cardiomyocyte hypertrophy.

Abstract 541: Dyxin/Lmcd1, A Novel LIM Protein, Is Both Necessary And Sufficient For The Induction Of Cardiomyocyte Hypertrophy

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Derk Frank ◽  
Christiane Hanselmann ◽  
Rainer Will ◽  
Hugo A Katus ◽  
Norbert Frey
Keyword(s):  
Cardiac Hypertrophy ◽  
Molecular Mechanisms ◽  
Mrna Level ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Hypertrophic Response ◽  
Lim Protein ◽  
A Genome ◽  
Necessary And Sufficient

Sustained cardiac hypertrophy may lead to heart failure and sudden death. While significant progress has been made in elucidating the underlying molecular mechanisms, it is believed that several molecules that modulate cardiomyocyte growth remain elusive. To identify novel candidates involved in hypertrophic signalling, we conducted a genome-wide screening experiment by subjecting neonatal rat cardiomyocytes (NRCM) to either biomechanical stretch or phenylephrine (PE) stimulation followed by microarray analyses. Among several other molecules (stretch: n=164; PE: n=238), the new LIM protein Dyxin/Lmcd1 was significantly upregulated both by stretch (5.6fold, p<0.001) and PE (2.5 fold, p<0.01). Moreover, Dyxin was markedly induced in hypertrophic hearts of transgenic mice overexpressing the phosphatase calcineurin (3.8fold on mRNA- and 2.9fold on protein level (both p<0.01)). To dissect the putative function of this novel molecule, we adenovirally overexpressed Dyxin in NRCM, which led to marked cellular hypertrophy (1.5fold increase in cell surface area, p<0.001) and induction of ANF (3.8fold, p<0.05). In addition, the calcineurin-responsive gene MCIP1.4 was found upregulated (3.2fold, p<0.001), suggesting that Dyxin activates the calcineurin pathway. In order to test whether Dyxin is also required for cardiomyocyte hypertrophy, we stimulated NRCVM with either PE or stretch and utilized adenovirus-encoded microRNAs to knock down Dyxin (−75% on protein, −85% on mRNA level). While both PE and stretch induced significant hypertrophy (+41% and +48%, p<0.001), the inhibition of Dyxin expression completely blunted the hypertrophic response to both stimuli (p<0.001). Consistently, induction of the “hypertrophic gene program” (including ANF, BNP, and alpha-skeletal actin) was abrogated. Likewise, PE-mediated upregulation of MCIP1.4 expression (7.3fold; p<0.001), was entirely prevented by the knockdown of Dyxin (0.8fold, p=n.s.). We show here that Dyxin, which has not been implicated in hypertrophy before, is significantly upregulated in cardiac hypertrophy. Moreover, it is both necessary and sufficient for cardiomyocyte hypertrophy, and this effect is mediated, at least in part by modulation of calcineurin signalling.

Upregulation of α-enolase protects cardiomyocytes from phenylephrine-induced hypertrophy

2018 ◽  
Vol 96 (4) ◽  
pp. 352-358
Author(s):  
Si Gao ◽  
Xue-ping Liu ◽  
Li-hua Wei ◽  
Jing Lu ◽  
Peiqing Liu
Keyword(s):  
Cardiac Hypertrophy ◽  
Glycolytic Enzyme ◽  
Pathological Process ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Abnormal Growth ◽  
Protein Levels ◽  
Neonatal Rat Cardiomyocytes ◽  
Abdominal Aortic

Cardiac hypertrophy often refers to the abnormal growth of heart muscle through a variety of factors. The mechanisms of cardiomyocyte hypertrophy have been extensively investigated using neonatal rat cardiomyocytes treated with phenylephrine. α-Enolase is a glycolytic enzyme with “multifunctional jobs” beyond its catalytic activity. Its possible contribution to cardiac dysfunction remains to be determined. The present study aimed to investigate the change of α-enolase during cardiac hypertrophy and explore its role in this pathological process. We revealed that mRNA and protein levels of α-enolase were significantly upregulated in hypertrophic rat heart induced by abdominal aortic constriction and in phenylephrine-treated neonatal rat cardiomyocytes. Furthermore, knockdown of α-enolase by RNA interference in cardiomyocytes mimicked the hypertrophic responses and aggravated phenylephrine-induced hypertrophy without reducing the total glycolytic activity of enolase. In addition, knockdown of α-enolase led to an increase of GATA4 expression in the normal and phenylephrine-treated cardiomyocytes. Our results suggest that the elevation of α-enolase during cardiac hypertrophy is compensatory. It exerts a catalytic independent role in protecting cardiomyocytes against pathological hypertrophy.

scholarly journals Differential activation of P-TEFb complexes in the development of cardiomyocyte hypertrophy following activation of distinct GPCRs

2020 ◽  
Author(s):  
Ryan D. Martin ◽  
Yalin Sun ◽  
Sarah MacKinnon ◽  
Luca Cuccia ◽  
Viviane Pagé ◽  
...  
Keyword(s):  
Gene Expression ◽  
Large Scale ◽  
Target Genes ◽  
Elongation Factor ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Rat Cardiomyocytes ◽  
Hypertrophic Response ◽  
Specific Regulation ◽  
Brd4 Inhibition

AbstractPathological cardiac hypertrophy is driven by neurohormonal activation of specific G protein-coupled receptors (GPCRs) in cardiomyocytes and is accompanied by large-scale changes in cardiomyocyte gene expression. These transcriptional changes require activity of positive transcription elongation factor b (P-TEFb), which is recruited to target genes by the bromodomain protein Brd4 or the Super Elongation Complex (SEC). Here we describe GPCR-specific regulation of these P-TEFb complexes and a novel mechanism for activating Brd4 in primary neonatal rat cardiomyocytes. The SEC was required for the hypertrophic response downstream of either the α1-adrenergic receptor (α1-AR) or the endothelin receptor (ETR). In contrast, Brd4 inhibition selectively impaired the α1-AR response. This was corroborated by the finding that activation of α1-AR, but not ETR, increased Brd4 occupancy at promoters and super enhancers of hypertrophic genes. Transcriptome analysis demonstrated that activation of both receptors initiated similar gene expression programs, but that Brd4 inhibition attenuated hypertrophic genes more robustly following α1-AR activation. Finally, we show that protein kinase A (PKA) is required for α1-AR stimulation of Brd4 chromatin occupancy. The differential role of the Brd4/P-TEFb complex in response to distinct GPCR pathways has potential clinical implications as therapies targeting this complex are currently being explored for heart failure.

scholarly journals JMJD1A Represses the Development of Cardiomyocyte Hypertrophy by Regulating the Expression of Catalase

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Rongjia Zang ◽  
Qingyun Tan ◽  
Fanrong Zeng ◽  
Dongwei Wang ◽  
Shuang Yu ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Natriuretic Peptide ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Mechanism Study ◽  
Aortic Constriction ◽  
Rat Cardiomyocytes ◽  
Protein Levels

The histone demethylase JMJD family is involved in various physiological and pathological functions. However, the roles of JMJD1A in the cardiovascular system remain unknown. Here, we studied the function of JMJD1A in cardiac hypertrophy. The mRNA and protein levels of JMJD1A were significantly downregulated in the hearts of human patients with hypertrophic cardiomyopathy and the hearts of C57BL/6 mice underwent cardiac hypertrophy induced by transverse aortic constriction (TAC) surgery or isoproterenol (ISO) infusion. In neonatal rat cardiomyocytes (NRCMs), siRNA-mediated JMJD1A knockdown facilitated ISO or angiotensin II-induced increase in cardiomyocyte size, protein synthesis, and expression of hypertrophic fetal genes, including atrial natriuretic peptide (Anp), brain natriuretic peptide (Bnp), and Myh7. By contrast, overexpression of JMJD1A with adenovirus repressed the development of ISO-induced cardiomyocyte hypertrophy. We observed that JMJD1A reduced the production of total cellular and mitochondrial levels of reactive oxygen species (ROS), which was critically involved in the effects of JMJD1A because either N-acetylcysteine or MitoTEMPO treatment blocked the effects of JMJD1A deficiency on cardiomyocyte hypertrophy. Mechanism study demonstrated that JMJD1A promoted the expression and activity of Catalase under basal condition or oxidative stress. siRNA-mediated loss of Catalase blocked the protection of JMJD1A overexpression against ISO-induced cardiomyocyte hypertrophy. These findings demonstrated that JMJD1A loss promoted cardiomyocyte hypertrophy in a Catalase and ROS-dependent manner.

scholarly journals Insulin-Induced Cardiomyocytes Hypertrophy That Is Prevented by Taurine via β-alanine-Sensitive Na+-Taurine Symporter

Nutrients ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 3686
Author(s):  
Ashley Jazzar ◽  
Danielle Jacques ◽  
Ghassan Bkaily
Keyword(s):  
Essential Amino Acid ◽  
Camp Response Element Binding ◽  
Cardiomyocyte Hypertrophy ◽  
Camp Response Element ◽  
Ventricular Cardiomyocytes ◽  
Element Binding Protein ◽  
Taurine Treatment ◽  
Pre Treatment ◽  
The Brain

Although insulin-induced cardiac hypertrophy is reported, very little information is available on the hypertrophic effect of insulin on ventricular cardiomyocytes and the regulation of sodium and calcium homeostasis. Taurine is a non-essential amino acid synthesized by cardiomyocytes and the brain and is present in low quantities in many foods, particularly seafood. The purpose of this study was to investigate whether chronic exposure to insulin induces hypertrophy of ventricular cardiomyocytes that are associated with changes in Na+ and Ca2+ homeostasis and whether taurine pre-treatment prevents these effects. Our results showed that chronic treatment with insulin leads to cardiomyocyte hypertrophy that is associated with an increase in basal intracellular Na+ and Ca2+ levels. Furthermore, long-term taurine treatment prevents morphological and ionic remodeling induced by insulin. In addition, blocking the Na+-taurine co-transporter prevented the taurine antihypertrophic effect. Finally, the insulin-induced remodeling of cardiomyocytes was associated with a decrease in the ratio of phospho-CREB (pCREB) to total cAMP response element binding protein (CREB); taurine prevented this effect. In conclusion, our results show that insulin induces ventricular cardiomyocyte hypertrophy via downregulation of the pCREB/tCREB level and that chronic taurine treatment prevents this effect.

Abstract 199: Distinctive Roles of Linker Histone H1 Variants in the Hypertrophic Response of Cardiomyocytes

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Michelle S Parvatiyar ◽  
Timothy D Lopez ◽  
Sarah Franklin ◽  
Thomas M Vondriska
Keyword(s):  
Histone H1 ◽  
Histone Variants ◽  
Linker Histone ◽  
Neonatal Rat ◽  
Cardiomyocyte Hypertrophy ◽  
Mrna Levels ◽  
Hypertrophic Response ◽  
Linker Histone H1 ◽  
Knock Down

Heart failure results when cardiac output is insufficient to meet physiological requirements and is often preceded by development of cardiomyocyte hypertrophy. As cardiac myocytes respond to hypertrophic stresses they re-express developmentally important genes, normally senescent in the adult. The chromatin structural events underlying this “fetal gene program” are unknown. We previously showed by proteomics that histones, components of the chromatin protein functional unit, the nucleosome, are altered during hypertrophic and failing phases of pressure overload in mouse: linker histone variants H1.2 and H1.5 decreased in hypertrophied myocardium while H1.0 increased during the transition to failure. The linker histone H1 family influences higher order chromatin structure and gene expression, although the role of this family in the heart is unknown. To assess the role of linker histones in hypertrophy, neonatal rat ventricular cardiomyocytes (NRVMs) were transfected with siRNAs individually targeting six H1 variants. Loss of H1.3 and H1.4 respectively induced a significant 26.1% (76 of 90) and 13.5% (80 of 94) increase in cell size area (µm2). A role of H1 in the hypertrophic response is evidenced by its influence on myosin heavy chain (MHC) mRNA expression. Knock-down of individual H1 variants significantly altered the MHC isoform ratio: loss of H1.3 increased α-MHC levels 1.5 fold and decreased β-MHC 1.6 fold while H1.5 depletion decreased α-MHC 2.5 fold. Both H1.3 and H1.4 knock-down increased atrial natriuretic factor (ANF) 1.3 fold while H1.5 loss decreased ANF 6.2 fold shown by qRT-PCR. Treatment with hypertrophy-inducing agents Isoproterenol (1μM), Endothelin (2nM) or Phenylephrine (10μM), reduced H1 mRNA levels however with subtle effects on protein abundance. To evaluate whether H1 loss shifted NRVM nuclei from a predominantly heterochromatic toward euchromatic state favoring gene accessibility we examined distinct histone markers of chromatin states. Histone H1.5 knock-down significantly decreased H3K9Me3 levels, a silencing mark associated with heterochromatin, 1.7 fold. Therefore we conclude that variants package distinctive regions of the genome and that H1.3 and H1.4 controls genes involved in the hypertrophic response.

scholarly journals S100A1 Enhances the L-type Ca2+ Current in Embryonic Mouse and Neonatal Rat Ventricular Cardiomyocytes

2005 ◽  
Vol 280 (43) ◽  
pp. 36019-36028 ◽  
Author(s):  
Michael Reppel ◽  
Philipp Sasse ◽  
Roland Piekorz ◽  
Ming Tang ◽  
Wilhelm Roell ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitor ◽  
Binding Protein ◽  
Neonatal Rat ◽  
Specific Expression ◽  
Rat Cardiomyocytes ◽  
Embryonic Mouse ◽  
Protein Levels ◽  
Ventricular Cardiomyocytes

S100A1 is an EF-hand type Ca2+-binding protein with a muscle-specific expression pattern. The highest S100A1 protein levels are found in cardiomyocytes, and it is expressed already at day 8 in the heart during embryonic development. Since S100A1 is known to be involved in the regulation of Ca2+ homeostasis, we tested whether extracellular S100A1 plays a role in regulating the L-type Ca2+ current (ICa) in ventricular cardiomyocytes. Murine embryonic (day 16.5 postcoitum) ventricular cardiomyocytes were incubated with S100A1 (0.001–10 μm) for different time periods (20 min to 48 h). ICa density was found to be significantly increased as early as 20 min (from –10.8 ± 1 pA/pF, n = 18, to –22.9 ± 1.4 pA/pF; +112.5 ± 13%, n = 9, p < 0.001) after the addition of S100A1 (1 μm). S100A1 also enhanced ICa current density in neonatal rat cardiomyocytes. Fluorescence and capacitance measurements evidenced a fast translocation of rhodamine-coupled S100A1 from the extracellular space into cardiomyocytes. S100A1 treatment did not affect cAMP levels. However, protein kinase inhibitor, a blocker of cAMP-dependent protein kinase A (PKA), abolished the S100A1-induced enhancement of ICa. Accordingly, measurements of PKA activity yielded a significant increase in S100A1-treated cardiomyocytes. In vitro reconstitution assays further demonstrated that S100A1 enhanced PKA activity. We conclude that the Ca2+-binding protein S100A1 augments transsarcolemmal Ca2+ influx via an increase of PKA activity in ventricular cardiomyocytes and hence represents an important regulator of cardiac function.

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