Abstract 3471: Ablation Of Phospholamban And Sarcolipin Has A Deleterious Effect On SERCA Pump Activity And Cardiac Contractility

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Mayilvahanan Shanmugam ◽  
Shumin Gao ◽  
Evangelia Kranias ◽  
Muthu Periasamy ◽  
Gopal J Babu
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Deleterious Effect ◽  
Contractile Function ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Double Knockout ◽  
Pump Activity ◽  
Serca Pump

Recent studies have been directed towards the potential therapeutic value of improving the sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) function in the failing myocardium. Overexpression of SERCA pump or inhibiting the function of phospholamban (PLB) has been shown to improve the cardiac function in failing myocardium. Towards this goal, we enhanced the SERCA pump activity in both atria and ventricle by ablating its key regulators, PLB and sarcolipin (SLN). The homozygous double knockout (dKO) pups were delivered in Mendelian ratio and reached adulthood without any visible abnormalities. However, these mice develop cardiac hypertrophy. The heart weight to body weight ratio significantly increased in 3– 4 months old dKO mice (WT-3.08±0.11 vs. dKO-4.14±0.14) and is associated with enlargement of myocytes (WT-117±8 μm2 vs. dKO-166±10 μm2). Ablation of PLB and SLN did not affect the expression of major Ca2+ handling proteins including SERCA2a, calsequestrin, L-type Ca2+ channel and ryanodine receptor in both atria and ventricles. Echocardiographic measurements showed increased diastolic (WT-0.90±0.02 mm vs. dKO-1.26±0.07 mm) and systolic (WT-1.33±0.03 mm vs. dKO-1.68±0.08 mm) septal wall thicknesses and diastolic (WT-0.91±0.02 mm vs. dKO-1.15±0.07 mm) and systolic (WT-1.15±0.03 mm vs. dKO-1.35±0.07 mm) post wall thickness in 3– 4 months old dKO mice hearts. However, left ventricular end-diastolic dimension (LVEDD), LV end-systolic dimension and ejection fraction (EF, %: WT-0.73±0.12 vs. dKO-0.69±0.03) are not very different from wildtype indicating preserved contractile function in the dKO mice. Our studies therefore suggest that the enhanced Ca2+ sensitivity of cardiac SERCA pump can progressively lead to cardiac hypertrophy and may have a deleterious effect on cardiac function during pathological conditions.

Abstract MP166: PRKAR1A Deficiency Abrogates Cardiac Hypertrophy Through Inhibition of Mitochondrial Fission

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yuening Liu ◽  
Peng Xia ◽  
Jingrui Chen ◽  
Patricia W Bandettini ◽  
Lawrence S Kirschner ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Postnatal Development ◽  
Contractile Function ◽  
Mitochondrial Fission ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Cardiac Complications ◽  
The Impact

Protein kinase A (PKA) is pivotal for cardiac function of human heart, and its dysregulation is involved with various cardiac pathologies. PKA regulatory subunit 1α (R1α, encoded by PRKAR1A gene) controls PKA kinase activity by sequestering the PKA catalytic subunits. Patients with PRKAR1A mutations are often diagnosed with Carney complex (CNC) and may die prematurely from cardiac complications such as heart failure. However, it remains unknown whether PRKAR1A deficiency interferes with normal heart growth during postnatal development. Here, we show that left ventricular mass is reduced in young CNC patients with PRKAR1A mutations or deletions. To investigate the impact of PRKAR1A deficiency on heart growth, we generated cardiac-specific PRKAR1A heterozygous knockout mice. Ablation of the PRKAR1A gene in mice increased cardiac PKA activity, reduced heart weight to body weight ratio and cardiomyocyte size without altering contractile function. Cardiomyocyte hypertrophy in response to activation of the α1-adrenergic receptor, was completely abolished by silencing of PRKAR1A . Mechanistically, depletion of PRKAR1A provoked PKA-dependent phosphorylation of the mitochondrial fission protein Drp1 at S637, resulting in impaired mitochondrial fission and diminished cardiomyocyte hypertrophy. In conclusion, PRKAR1A deficiency abrogates cardiac hypertrophy during postnatal development, likely through inhibiting Drp1-mediated mitochondrial fission. Our study provides novel mechanistic insights regarding the cardiac mortality associated with CNC.

scholarly journals PKC-β is not necessary for cardiac hypertrophy

2001 ◽  
Vol 280 (5) ◽  
pp. H2264-H2270 ◽  
Author(s):  
Brian B. Roman ◽  
David L. Geenen ◽  
Michael Leitges ◽  
Peter M. Buttrick
Keyword(s):  
Cardiac Hypertrophy ◽  
Gene Knockout ◽  
Weight Ratio ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Heart Weight ◽  
Hypertrophic Response ◽  
Pathological Hypertrophy ◽  
Pkc Β ◽  
And Control

Studies in human and rodent models have shown that activation of protein kinase C-β (PKC-β) is associated with the development of pathological hypertrophy, suggesting that ablation of the PKC-β pathway might prevent or reverse cardiac hypertrophy. To explore this, we studied mice with targeted disruption of the PKC-β gene (knockout, KO). There were no detectable differences in expression or distribution of other PKC isoforms between the KO and control hearts as determined by Western blot analysis. Baseline hemodynamics were measured using a closed-chest preparation and there were no differences in heart rate and arterial or left ventricular pressure. Mice were subjected to two independent hypertrophic stimuli: phenylephrine (Phe) at 20 mg · kg−1 · day−1 sq infusion for 3 days, and aortic banding (AoB) for 7 days. KO animals demonstrated an increase in heart weight-to-body weight ratio (Phe, 4.3 ± 0.6 to 6.1 ± 0.4; AoB, 4.0 ± 0.1 to 5.8 ± 0.7) as well as ventricular upregulation of atrial natriuretic factor mRNA analogous to those seen in control animals. These results demonstrate that PKC-β expression is not necessary for the development of cardiac hypertrophy nor does its absence attenuate the hypertrophic response.

Transient outward current in catecholamine-induced cardiac hypertrophy in the rat

1996 ◽  
Vol 271 (6) ◽  
pp. H2360-H2367 ◽  
Author(s):  
J. Meszaros ◽  
K. O. Ryder ◽  
G. Hart
Keyword(s):  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Outward Current ◽  
Cell Voltage ◽  
Underlying Mechanism ◽  
Left Ventricular ◽  
Daily Injection ◽  
Heart Weight ◽  
Inactivation Kinetics ◽  
Transient Outward Current

We have demonstrated that a daily injection of isoproterenol (5 mg/kg ip) for 7 days induces a 30% increment in heart weight-to-body weight ratio and prolongs the action potential duration (APD) in male Wistar rats. The underlying mechanism of the prolonged APD was investigated in this model of hypertrophy by measuring the transient outward potassium current (Ito) in left ventricular myocytes of the rat with whole cell voltage-clamp techniques. Cell membrane capacitance was increased by 39%: 122 +/- 3 (n = 23) and 171 +/- 5 (SE) pF (n = 20) in control and hypertrophy, respectively (P < 0.001). Ito was evoked in sodium-free solutions containing 0.5 mM Ca2+ and 2 mM Co2+ by step depolarizations from a holding potential of -80 mV. The amplitude of the 4-aminopyridine-sensitive Ito (at 70 mV) was reduced by 28% in hypertrophy: 3.2 +/- 0.3 (n = 23) and 2.3 +/- 0.4 (SE) nA (n = 20) in control and hypertrophy, respectively (P < 0.05). When normalized for cell capacitance, the reduction was much larger: 26.4 +/- 2.5 and 13.1 +/- 1.8 pA/pF in control and hypertrophy, respectively (P < 0.001). The voltage dependence of Ito was similar in both cell types. No change was observed in the steady-state activation and inactivation kinetics in the two groups, nor was there a change in the time dependence of inactivation. The recovery from inactivation of Ito when fitted with a monoexponential function was not changed significantly in hypertrophy: time constants = 8.2 +/- 0.4 (n = 13) and 8.3 +/- 0.3 ms (n = 12) in control and hypertrophy, respectively. These results show that Ito density is decreased in catecholamine-induced cardiac hypertrophy, but current kinetics are not affected. The reduced Ito density may underlie the prolongation of APD in this model of hypertrophy.

S6K inhibition renders cardiac protection against myocardial infarction through PDK1 phosphorylation of Akt

2011 ◽  
Vol 441 (1) ◽  
pp. 199-207 ◽  
Author(s):  
Ruomin Di ◽  
Xiangqi Wu ◽  
Zai Chang ◽  
Xia Zhao ◽  
Qiuting Feng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Cardiac Remodelling ◽  
Heart Weight ◽  
S6 Kinase ◽  
Beneficial Effects ◽  
Therapeutic Value ◽  
Specific Deletion

In the present study, we observed a rapid and robust activation of the ribosomal protein S6K (S6 kinase) provoked by MI (myocardial infarction) in mice. As activation of S6K promotes cell growth, we hypothesized that increased S6K activity contributes to pathological cardiac remodelling after MI and that suppression of S6K activation may prevent aberrant cardiac remodelling and improve cardiac function. In mice, administration of rapamycin effectively suppressed S6K activation in the heart and significantly improved cardiac function after MI. The heart weight/body weight ratio and fibrotic area were substantially reduced in rapamycin-treated mice. In rapamycin-treated mice, decreased cardiomyocyte remodelling and cell apoptosis were observed compared with vehicle-treated controls. Consistently, inhibition of S6K with PF-4708671 displayed similar protection against MI as rapamycin. Mechanistically, we observed significantly enhanced Thr308 phosphorylation and activation of Akt in rapamycin- and PF-4708671-treated hearts. Cardiomyocyte-specific deletion of PDK1 (phosphoinositide-dependent kinase 1) and Akt1/3 abolished cardioprotection after MI in the presence of rapamycin administration. These results demonstrate that S6K inhibition rendered beneficial effects on left ventricular function and alleviated adverse remodelling following MI in mice by enhancing Akt signalling, suggesting the therapeutic value of both rapamycin and PF-4708671 in treating patients following an MI.

A neutralizing leptin receptor antibody mitigates hypertrophy and hemodynamic dysfunction in the postinfarcted rat heart

2008 ◽  
Vol 295 (1) ◽  
pp. H441-H446 ◽  
Author(s):  
Daniel M. Purdham ◽  
Venkatesh Rajapurohitam ◽  
Asad Zeidan ◽  
Cathy Huang ◽  
Garrett J. Gross ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Leptin Receptor ◽  
Diastolic Pressure ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Receptor Blockade ◽  
Receptor Antibody ◽  
Postinfarction Remodeling

The 16 kDa adipokine leptin has been shown to exert direct hypertrophic effects on cultured cardiomyocytes although its role as an endogenous contributor to postinfarction remodeling and heart failure has not been determined. We therefore investigated the effect of leptin receptor blockade in vivo on hemodynamic function and cardiac hypertrophy following coronary artery ligation (CAL). Cardiac function and biochemical parameters were measured in rats subjected to 7 or 28 days of left main CAL in the presence and absence of a leptin receptor antibody. Animals subjected to an identical treatment in which the artery was not tied served as sham-operated controls. CAL produced myocardial hypertrophy, which was most pronounced 28 days postinfarction as demonstrated by increases in both left ventricular weight-to-body weight ratio and atrial natriuretic peptide gene expression, both of which were abrogated by leptin receptor antagonism. Leptin receptor blockade also significantly improved left ventricular systolic function, attenuated the increased left ventricular end-diastolic pressure, and reduced the expression of genes associated with extracellular matrix remodeling 28 days following CAL. In conclusion, the ability of a leptin receptor-neutralizing antibody to improve cardiac function offers evidence that endogenous leptin contributes to cardiac hypertrophy following CAL. The possibility exists that targeting the myocardial leptin receptor represents a viable and novel approach toward attenuating postinfarction remodeling.

scholarly journals Elevated myocardial Na+/H+ exchanger isoform 1 activity elicits gene expression that leads to cardiac hypertrophy

2010 ◽  
Vol 42 (3) ◽  
pp. 374-383 ◽  
Author(s):  
Jin Xue ◽  
Fatima Mraiche ◽  
Dan Zhou ◽  
Morris Karmazyn ◽  
Tatsujiro Oka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Interstitial Fibrosis ◽  
Gene Activation ◽  
Weight Ratio ◽  
Heart Weight ◽  
Peroxisome Proliferator ◽  
Cross Sectional

In myocardial disease, elevated expression and activity of Na+/H+ exchanger isoform 1 (NHE1) are detrimental. To better understand the involvement of NHE1, transgenic mice with elevated heart-specific NHE1 expression were studied. N-line mice expressed wild-type NHE1, and K-line mice expressed activated NHE1. Cardiac morphology, interstitial fibrosis, and cardiac function were examined by histological staining and echocardiography. Differences in gene expression between the N-line or K-line and nontransgenic littermates were probed with genechip analysis. We found that NHE1 K-line (but not N-line) hearts developed hypertrophy, including elevated heart weight-to-body weight ratio and increased cross-sectional area of the cardiomyocytes, interstitial fibrosis, as well as depressed cardiac function. N-line hearts had modest changes in gene expression (50 upregulations and 99 downregulations, P < 0.05), whereas K-line hearts had a very strong transcriptional response (640 upregulations and 677 downregulations, P < 0.05). In addition, the magnitude of expression alterations was much higher in K-line than N-line mice. The most significant changes in gene expression were involved in cardiac hypertrophy, cardiac necrosis/cell death, and cardiac infarction. Secreted phosphoprotein 1 and its signaling pathways were upregulated while peroxisome proliferator-activated receptor γ signaling was downregulated in K-line mice. Our study shows that expression of activated NHE1 elicits specific pathways of gene activation in the myocardium that lead to cardiac hypertrophy, cell death, and infarction.

scholarly journals Protocatechuic acid attenuates isoproterenol-induced cardiac hypertrophy via downregulation of ROCK1–Sp1–PKCγ axis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Liyan Bai ◽  
Hae Jin Kee ◽  
Xiongyi Han ◽  
Tingwei Zhao ◽  
Seung-Jung Kee ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Acid Treatment ◽  
Protocatechuic Acid ◽  
Therapeutic Potential ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Transcriptional Level ◽  
Cell Area ◽  
Protective Effects

AbstractCardiac hypertrophy is an adaptive response of the myocardium to pressure overload or adrenergic agonists. Here, we investigated the protective effects and the regulatory mechanism of protocatechuic acid, a phenolic compound, using a mouse model of isoproterenol-induced cardiac hypertrophy. Our results demonstrated that protocatechuic acid treatment significantly downregulated the expression of cardiac hypertrophic markers (Nppa, Nppb, and Myh7), cardiomyocyte size, heart weight to body weight ratio, cross-sectional area, and thickness of left ventricular septum and posterior wall. This treatment also reduced the expression of isoproterenol-induced ROCK1, Sp1, and PKCγ both in vivo and in vitro. To investigate the mechanism, we performed knockdown and overexpression experiments. The knockdown of ROCK1, Sp1, or PKCγ decreased the isoproterenol-induced cell area and the expression of hypertrophic markers, while the overexpression of Sp1 or PKCγ increased the levels of hypertrophic markers. Protocatechuic acid treatment reversed these effects. Interestingly, the overexpression of Sp1 increased cell area and induced PKCγ expression. Furthermore, experiments using transcription inhibitor actinomycin D showed that ROCK1 and Sp1 suppression by protocatechuic acid was not regulated at the transcriptional level. Our results indicate that protocatechuic acid acts via the ROCK1/Sp1/PKCγ axis and therefore has promising therapeutic potential as a treatment for cardiac hypertrophy.

Myocardial metabolic and functional responses to acetylcholine are altered in thyroxine-induced cardiac hypertrophy

1995 ◽  
Vol 73 (6) ◽  
pp. 729-735 ◽  
Author(s):  
Harvey R. Weiss ◽  
James Tse
Keyword(s):  
Blood Flow ◽  
Cardiac Hypertrophy ◽  
Muscarinic Receptor ◽  
Coronary Blood Flow ◽  
Muscarinic Receptors ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Receptor Density ◽  
Functional Responses

We tested the hypothesis that acetylcholine would reduce myocardial O2 consumption and function, and that thyroxine (T4, 0.5 mg/kg for 16 days) induced cardiac hypertrophy would change this relationship. Anesthetized open-chest New Zealand white rabbits were divided into four groups: control–vehicle (CV, n = 8), control–acetylcholine (CA, n = 10), T4–vehicle (T4V, n = 9), and T4-acetylcholine (T4A, n = 10). Either vehicle or acetylcholine (10−3 M) was topically applied to the left ventricular surface. Coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry) were used to determine O2 consumption, and muscarinic receptor density and affinity were also determined. T4 increased the heart weight/body weight ratio from 2.6 ± 0.1 to 3.4 ± 0.1. T4-treated animals had higher heart rates, blood pressures, and left ventricular dP/dtmax than control rabbits. Topical acetylcholine depressed hemodynamic parameters with a greater decrement in pressures and cardiac output in the T4A group (CA, −25%, T4A, −40%). Myocardial O2 consumption and coronary blood flow were higher in the T4-treated hearts. Myocardial O2 consumption significantly declined in both groups during acetylcholine, but the reduction was greater in the T4-treated hearts (CV 7.9 ± 0.4 to CA 5.8 ± 0.6 and T4V 18.8 ± 3.0 to T4A 7.3 ± 1.0 mL O2∙min−1∙100 g−1). Muscarinic receptor density (Bmax) was elevated by 41% in the T4-treated hearts, but affinity (Kd) was not altered. Thus, the T4-treated hearts responded to acetylcholine to a greater extent than control hearts in terms of functional and O2 consumption decrements. This may, in part, be related to the elevated number of muscarinic receptors in the T4-treated rabbit hearts.Key words: thyroxine, cardiac hypertrophy, acetylcholine, muscarinic receptors, coronary blood flow, myocardial O2 consumption, rabbit.

Polydatin attenuates cardiac hypertrophy through modulation of cardiac Ca2+ handling and calcineurin-NFAT signaling pathway

2014 ◽  
Vol 307 (5) ◽  
pp. H792-H802 ◽  
Author(s):  
Wenwen Ding ◽  
Ming Dong ◽  
Jianxin Deng ◽  
Dewen Yan ◽  
Yun Liu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Cardiac Contractility ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Neonatal Rat ◽  
Therapeutic Effects ◽  
Calcineurin Activity ◽  
Calcineurin Pathway

Polydatin (PD), a resveratrol glucoside extracted from the perennial herbage Polygonum cuspidatum, has been suggested to have wide cardioprotective effects. This study aimed to explore the direct antihypertrophic role of PD in cultured neonatal rat ventricular myocytes (NRVMs) and its therapeutic effects against pressure overload (PO)-induced hypertrophic remodeling and heart failure. Furthermore, we investigated the mechanisms underlying the actions of PD. Treatment of NRVMs with phenylephrine for 72 h induced myocyte hypertrophy, where the cell surface area and protein levels of atrial natriuretic peptide and β-myosin heavy chain (β-MHC) were significantly increased. The amplitude of systolic Ca2+ transient was increased, and sarcoplasmic reticulum Ca2+ recycling was prolonged. Concomitantly, calcineurin activity was increased and NFAT protein was imported into the nucleus. PD treatment restored Ca2+ handling and inhibited calcineurin-NFAT signaling, thus attenuating the hypertrophic remodeling in NRVMs. PO-induced cardiac hypertrophy was produced by transverse aortic constriction (TAC) in C57BL/6 mice, where the left ventricular posterior wall thickness and heart-to-body weight ratio were significantly increased. The cardiac function was increased at 5 wk of TAC, but significantly decreased at 13 wk of TAC. The amplitude of Ca2+ transient and calcineurin activity were increased at 5 wk of TAC. PD treatment largely abolished TAC-induced hypertrophic remodeling by inhibiting the Ca2+-calcineurin pathway. Surprisingly, PD did not inhibit myocyte contractility despite that the amplitude of Ca2+ transient was decreased. The cardiac function remained intact at 13 wk of TAC. In conclusion, PD is beneficial against PO-induced cardiac hypertrophy and heart failure largely through inhibiting the Ca2+-calcineurin pathway without compromising cardiac contractility.

Genistein prevents isoproterenol-induced cardiac hypertrophy in rats

2012 ◽  
Vol 90 (8) ◽  
pp. 1117-1125 ◽  
Author(s):  
Subir Kumar Maulik ◽  
Pankaj Prabhakar ◽  
Amit Kumar Dinda ◽  
Sandeep Seth
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Body Weight ◽  
Nitric Oxide Synthase ◽  
Cardiac Hypertrophy ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Heart Weight ◽  
Once Daily ◽  
Oxide Synthase

Genistein, an isoflavone and a rich constituent of soy, possesses important regulatory effects on nitric oxide (NO) synthesis and oxidative stress. Transient and low release of NO by endothelial nitric oxide synthase (eNOS) has been shown to be beneficial, while high and sustained release by inducible nitric oxide synthase (iNOS) may be detrimental in pathological cardiac hypertrophy. The present study was designed to evaluate whether genistein could prevent isoproterenol-induced cardiac hypertrophy in male Wistar rats (150–200 g, 10–12 weeks old) rats. Isoproterenol (5 mg·(kg body weight)–1) was injected subcutaneously once daily for 14 days to induced cardiac hypertrophy. Genistein (0.1 and 0.2 mg·kg–1, subcutaneous injection once daily) was administered along with isoproterenol. Heart tissue was studied for myocyte size and fibrosis. Myocardial thiobarbituric acid reactive substances (TBARS), glutathione (GSH), superoxide dismutase (SOD), catalase levels, and 1-OH proline (collagen content) were also estimated. Genistein significantly prevented any isoproterenol-induced increase in heart weight to body weight ratio, left ventricular mass (echocardiographic), myocardial 1-OH proline, fibrosis, myocyte size and myocardial oxidative stress. These beneficial effects of genistein were blocked by a nonselective NOS inhibitor (L-NAME), but not by a selective iNOS inhibitor (aminoguanidine). Thus, the present study suggests that the salutary effects of genistein on isoproterenol-induced cardiac hypertrophy may be mediated through inhibition of iNOS and potentiation of eNOS activities.

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