Biomedical subjects

Yibin Wang

Publications and source records attributed to Yibin Wang.

At least 19 recordsLinked to original sources

PubMed2007

Oral-intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects.

OBJECTIVE: The pharmacokinetics and lymphocyte responses to the immunomodulator fingolimod (FTY720) were characterized after oral and intravenous administration. METHODS: In this randomized, two-period crossover study 11 evaluable healthy subjects received single doses of fingolimod 1.25 mg orally and 1 mg intravenously infused over 2 h. The pharmacokinetics of fingolimod, blood lymphocyte counts and heart rate were characterized for 28 days after each dose. RESULTS: After oral administration, Cmax was 1.1+/-0.2 ng/ml occurring at 12 h postdose and the AUC was 201+/-31 ng.h/ml. After intravenous infusion, Cmax was 4.9+/-0.8 ng/ml, AUC was 175+/-50 ng. h/ml, clearance was 6.3+/-2.3 l/h and distribution volume was 1199+/-260 l. The oral/intravenous ratio of dose-normalized AUCs was 0.94 (95%CI: 0.78-1.12). The pharmacologically active metabolite fingolimod-phosphate was quantifiable near its peak after oral administration but not after intravenous administration. The mean lymphocyte nadir occurred on day 1 and was 35% lower after oral (0.74x10(9)/l) than after intravenous (1.15x10(9)/l) administration. Lymphocytes recovered to the normal range by day 15 for both treatments. The mean heart rate nadir occurred 3-4 h postdose and was 11% lower after oral administration (47 bpm) versus intravenous administration (53 bpm). CONCLUSIONS: Average systemic exposure to fingolimod was similar after oral and intravenous administration. However, the acute decrease in lymphocyte counts was weaker after intravenous administration, likely because of lower blood levels of the active metabolite fingolimod-phosphate compared with oral administration.

Administration, Oral↗

PubMed2007

Dose-proportional pharmacokinetics of d-threo-methylphenidate after a repeated-action release dosage form.

A bimodal extended-release formulation of d-methylphenidate (d-MPH) has been developed to enable fast onset of action and once-daily administration in patients with attention deficit hyperactivity disorder. The authors studied the dose proportionality of extended-release d-MPH pharmacokinetics. Twenty-five healthy adult volunteers received 5, 10, 20, 30, and 40 mg d-MPH in a crossover study with 7 days between doses. All doses were well tolerated. Dose proportionality was shown for all dose-dependent pharmacokinetic parameters. Geometric means (%gCV) for the first Cmax peak, Cmax0-4, were 3.25 (29.0%), 6.05 (27.1%), 12.6 (31.9%), 18.5 (31.9%), and 25.2 ng/mL (29.3%) for d-MPH 5, 10, 20, 30, and 40 mg, respectively. Geometric means (%gCV) for Cmax4-10 were 3.18 (27.5%), 5.84 (27.7%), 12.5 (31.7%), 17.7 (31.6%), and 23.6 ng/mL (29.0%), respectively. Geometric means for AUC(0-infinity) were 24.3 (30.7%), 45.9 (30.2%), 96.4 (35.5%), 144 (33.3%), and 195 ng x h/mL (30.9%), respectively. The pharmacokinetics of once-daily extended-release d-MPH are proportional to the dose.

Administration, Oral↗

PubMed2006

Pressure overload induces greater hypertrophy and mortality in female mice with p38alpha MAPK inhibition.

We examined pressure overload left ventricular (LV) hypertrophy (H) induced by aortic banding in transgenic mice with cardiac-specific expression of a dominant negative (DN) p38alpha (TG) and wild type controls (WT). In response to chronic pressure overload, induced by aortic constriction, LV/BW increased more, p<0.05, in female TG (6.4+/-0.2, n=7) than in WT female (5.1+/-0.2, n=10), or male TG or WT (5.0+/-0.2, n=10 vs. 5.5+/-0.2, n=8). Lung/BW, an index of LV decompensation, was significantly higher, p<0.05, in banded female TG (14+/-1.2 mg/g) than in WT females (9.0+/-0.8), or male TG or WT (8.2+/-0.7 vs. 9.3+/-1.3). This was associated with higher premature mortality, p<0.05, in banded female TG mice (42%) compared with banded WT females (10%), TG males (13%), or WT males (17%). In male, but not female, TG mice, the number of TUNEL-positive cells was smaller, p<0.05, compared with WT. Phospho-Akt kinase activity increased (p<0.05) in female TG after banding, but not in males. After ovariectomy, chronic pressure overload no longer induced greater mortality, greater LVH, or p-Akt levels in female TG mice, and like male TG mice, apoptosis was protected. DN-p38alpha enhanced estrogen-induced activation of Akt in cultured cardiac myocytes. Thus, inhibition of p38alpha MAPK paradoxically augments LVH resulting in cardiac decompensation and increased mortality in response to pressure overload more in female mice than male mice, which could be due to increased Akt activation and/or through cross-talk between p38alpha MAPK and Akt.

Animals↗

PubMed2006

Overexpression of bone morphogenetic protein 10 in myocardium disrupts cardiac postnatal hypertrophic growth.

Postnatal cardiac hypertrophies have traditionally been classified into physiological or pathological hypertrophies. Both of them are induced by hemodynamic load. Cardiac postnatal hypertrophic growth is regarded as a part of the cardiac maturation process that is independent of the cardiac working load. However, the functional significance of this biological event has not been determined, mainly because of the difficulty in creating an experimental condition for testing the growth potential of functioning heart in the absence of hemodynamic load. Recently, we generated a novel transgenic mouse model (alphaMHC-BMP10) in which the cardiac-specific growth factor bone morphogenetic protein 10 (BMP10) is overexpressed in postnatal myocardium. These alphaMHC-BMP10 mice appear to have normal cardiogenesis throughout embryogenesis, but develop to smaller hearts within 6 weeks after birth. alphaMHC-BMP10 hearts are about half the normal size with 100% penetrance. Detailed morphometric analysis of cardiomyocytes clearly indicated that the compromised cardiac growth in alphaMHC-BMP10 mice was solely because of defect in cardiomyocyte postnatal hypertrophic growth. Physiological analysis further demonstrated that the responses of these hearts to both physiological (e.g. exercise-induced hypertrophy) and pathological hypertrophic stimuli remain normal. In addition, the alphaMHC-BMP10 mice develop subaortic narrowing and concentric myocardial thickening without obstruction by four weeks of age. Systematic analysis of potential intracellular pathways further suggested a novel genetic pathway regulating this previously undefined cardiac postnatal hypertrophic growth event. This is the first demonstration that cardiac postnatal hypertrophic growth can be specifically modified genetically and dissected out from physiological and pathological hypertrophies.

Animals↗

PubMed2006

JNK activation decreases PP2A regulatory subunit B56alpha expression and mRNA stability and increases AUF1 expression in cardiomyocytes.

A central feature of heart disease is a molecular remodeling of signaling pathways in cardiac myocytes. This study focused on novel molecular elements of MAPK-mediated alterations in the pattern of gene expression of the protein phosphatase 2A (PP2A). In an established model of sustained JNK activation, a 70% decrease in expression of the targeting subunit of PP2A, B56alpha, was observed in either neonatal or adult cardiomyocytes. This loss in protein abundance was accompanied by a decrease of 69% in B56alpha mRNA steady-state levels. Given that the 3'-untranslated region of this transcript contains adenylate-uridylate-rich elements known to regulate mRNA degradation, experiments explored the notion that instability of B56alpha mRNA accounts for the response. mRNA time-course analyses with real-time PCR methods showed that B56alpha transcript was transformed from a stable (no significant decay over 1 h) to a labile form that rapidly degraded within minutes. These results were supported by complementary experiments that revealed that the RNA-binding protein AUF1, known to destabilize target mRNA, was increased fourfold in JNK-activated cells. A variety of other stress-related stimuli, such as p38 MAPK activation and phorbol ester, upregulated AUF1 expression in cultured cardiac cells as well. In addition, gel mobility shift assays demonstrated that p37AUF1 binds with nanomolar affinity to segments of the B56alpha 3'-untranslated region. Thus these studies provide new evidence that signaling-induced mRNA instability is an important mechanism that underlies the changes in the pattern of gene expression evoked by stress-activated pathways in cardiac cells.

3' Untranslated Regions↗

PubMed2006

Myocardin induces cardiomyocyte hypertrophy.

In response to stress signals, postnatal cardiomyocytes undergo hypertrophic growth accompanied by activation of a fetal gene program, assembly of sarcomeres, and cellular enlargement. We show that hypertrophic signals stimulate the expression and transcriptional activity of myocardin, a cardiac and smooth muscle-specific coactivator of serum response factor (SRF). Consistent with a role for myocardin as a transducer of hypertrophic signals, forced expression of myocardin in cardiomyocytes is sufficient to substitute for hypertrophic signals and induce cardiomyocyte hypertrophy and the fetal cardiac gene program. Conversely, a dominant-negative mutant form of myocardin, which retains the ability to associate with SRF but is defective in transcriptional activation, blocks cardiomyocyte hypertrophy induced by hypertrophic agonists such as phenylephrine and leukemia inhibitory factor. Myocardin-dependent hypertrophy can also be partially repressed by histone deacetylase 5, a transcriptional repressor of myocardin. These findings identify myocardin as a nuclear effector of hypertrophic signaling pathways that couples stress signals to a transcriptional program for postnatal cardiac growth and remodeling.

Animals↗

PubMed2006

Differentiation of innovator versus generic cyclosporine via a drug interaction on sirolimus.

OBJECTIVE: Both sirolimus and cyclosporine are immunosuppressants used in a combined regimen after organ transplantation. When coadministered with the innovator formulation of cyclosporine, sirolimus blood levels increase 3.3-fold due to a pharmacokinetic interaction. We assessed this drug interaction for potential differences when the innovator formulation is replaced by a generic cyclosporine. METHODS: In this randomized single-dose crossover study, 28 healthy subjects received 5 mg sirolimus oral solution with 250 mg cyclosporine soft gelatin capsules given as the innovator formulation (reference treatment) versus a generic formulation (test treatment). Sirolimus peak blood concentration (Cmax) and area under the concentration-time curve (AUC) were compared between test and reference treatments by standard bioequivalence testing. RESULTS: Sirolimus Cmax was significantly lower by 17% in the presence of generic versus innovator cyclosporine (p=0.0003) and failed bioequivalence criteria with a test/reference ratio of 0.83 (90% confidence interval, 0.77-0.90). Nearly half of the subjects (46%) had sirolimus Cmax changes which fell outside the bioequivalence window with individual Cmax decreases up to 52% and increases up to 39%. Sirolimus AUC was significantly lower by 11% in the presence of generic versus innovator cyclosporine (p=0.041) but satisfied average bioequivalence criteria with a test/reference ratio of 0.89 (0.83-0.95). Nonetheless, over a third of the subjects (43%) had sirolimus AUC changes outside the standard bioequivalence window with individual AUC decreases up to 39% and increases up to 42%. CONCLUSIONS: Switching between innovator and generic cyclosporine may have a clinically-relevant impact on coadministered sirolimus pharmacokinetics. If such a switch is initiated by the prescriber, follow-up therapeutic monitoring of both cyclosporine and sirolimus blood levels should be performed to guide dose adjustments as necessary. If the switch is made without consulting the prescriber, potentially significant changes in sirolimus exposure could go unnoticed by the clinician and patient.

Adult↗

PubMed2006

Heart hypertrophy during pregnancy: a better functioning heart?

During pregnancy, healthy women develop ventricular hypertrophy and diastolic dysfunction as a result of volume overload as well as increased stretch and force demand. Pregnancy also induces electrocardiogram disturbances such as longer QT-interval dispersion. Surprisingly, it was not until recently that the underlying molecular mechanisms or the role of sex hormones was addressed in this critical female reproductive stage. Recent work with the use of mouse and rat models show that the molecular signature of pregnancy-related hypertrophy differs from that of a pathologic form in that classic gene markers (e.g., myosin heavy chains [alpha and beta], atrial natriuretic peptide, phospholamban, and sarcoplasmic reticulum Ca(2+)-ATPase) remain unchanged. However, both types of hypertrophies have the commonality of a reduced expression of the Kv4.3 channel, a membrane protein that can prevent cardiac hypertrophy when overexpressed. Increased estrogen in late pregnancy may be a mechanism to induce Kv4.3 protein downregulation and increased activity of the stretch-activated c-Src kinase. Cellular/molecular mechanisms used to make a pregnant woman's heart work more efficiently and recover to normal cardiac function postpartum are beginning to emerge as cardioprotective natriuretic peptides- and NO-cGMP cascades get upregulated postpartum. This exciting initial work calls for more research in this underexplored area that should set the basis for better treatment of women during pregnancy.

Animals↗

PubMed2006

Average bioequivalence evaluation: general methods for pilot trials.

In clinical development of a bioequivalent (BE) drug product, a two-step strategy is commonly adopted. In the first step, a pilot BE trial is conducted to evaluate the acceptability of the test drug product as a candidate for further evaluation in a subsequent pivotal BE trial. In the second step, a full-scale pivotal BE trial is conducted to formally establish bioequivalence. The objective and criterion of a pilot BE trial are different from those of a pivotal BE trial. In practice, however, a pilot BE trial is often inappropriately designed and analyzed based on the criterion for a pivotal BE trial. One main reason is the lack of well-established design and analysis methods for a pilot BE trial. To close this gap in practice, this study proposes a Pilot Acceptance Range method specfically constructed for analyzing a pilot BE trial within the framework of a two-step strategy. For designing a crossover pilot BE trial, this paper derives the power function and provides an easy-to-use method for determining the sample size.

Clinical Trials as Topic↗

PubMed2006

FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects.

The purpose of this double-blind, placebo-controlled study was to measure the effects of FTY720, a novel immunomodulator, on heart rate and rhythm in healthy volunteers. Subjects (n = 66) were randomized to FTY720 1.25 mg or 5 mg or placebo administered once daily for 7 days. Continuous telemetry revealed an acute, dose-dependent decrease in mean heart rate (10-bpm decrease vs placebo) following the first dose of FTY720, with a nadir generally 4 hours postdose. Although a persistent FTY720-related decrease in heart rate was measured from day 2 to day 7, additional doses of FTY720 after day 2 resulted in no further incremental decreases. Mean PR interval increased by approximately 8 to 10 msec in FTY720-treated subjects on day 1. FTY720 did not increase the QRS or QT interval. These results confirm that the first dose of FTY720 has a mild to moderate negative chronotropic effect.

Adolescent↗

PubMed2005

TAB-1 modulates intracellular localization of p38 MAP kinase and downstream signaling.

Stress-activated mitogen-activated protein (MAP) kinase p38 mediates stress signaling in mammalian cells via threonine and tyrosine phosphorylation in its conserved TGY motif by upstream MAP kinase kinases (MKKs). In addition, p38 MAP kinase can also be activated by an MKK-independent mechanism involving TAB-1 (TAK-1-binding protein)-mediated autophosphorylation. Although TAB-1-mediated p38 activation has been implicated in ischemic heart, the biological consequences and downstream signaling of TAB-1-mediated p38 activation in cardiomyocytes is largely unknown. We show here that TAB-1 expression leads to a significant induction of p38 autophosphorylation and consequent kinase activation in cultured neonatal cardiomyocytes. In contrast to MKK3-induced p38 kinase downstream effects, TAB-1-induced p38 kinase activation does not induce expression of pro-inflammatory genes, cardiac marker gene expression, or changes in cellular morphology. Rather, TAB-1 binds to p38 and prevents p38 nuclear localization. Furthermore, TAB-1 disrupts p38 interaction with MKK3 and redirects p38 localization in the cytosol. Consequently, TAB-1 expression antagonizes the downstream activity of p38 kinase induced by MKK3 and attenuates interleukin-1beta-induced inflammatory gene induction in cardiomyocytes. These data suggest that TAB-1 can mediate MKK-independent p38 kinase activation while negatively modulating MKK-dependent p38 function. Our study not only redefines the functional role of TAB-1 in p38 kinase-mediated signaling pathways but also provides the first evidence that intracellular localization of p38 kinase and complex interaction dictates its downstream effects. These results suggest a previously unknown mechanism for stress-MAP kinase regulation in mammalian cells.

Animals↗

PubMed2005

Distinct gene expression profiles in adult mouse heart following targeted MAP kinase activation.

Three major MAP kinase signaling cascades, ERK, p38, and JNK, play significant roles in the development of cardiac hypertrophy and heart failure in response to external stress and neural/hormonal stimuli. To study the specific function of each MAP kinase branch in adult heart, we have generated three transgenic mouse models with cardiac-specific and temporally regulated expression of activated mutants of Ras, MAP kinase kinase (MKK)3, and MKK7, which are selective upstream activators for ERK, p38, and JNK, respectively. Gene expression profiles in transgenic adult hearts were determined using cDNA microarrays at both early (4-7 days) and late (2-4 wk) time points following transgene induction. From this study, we revealed common changes in gene expression among the three models, particularly involving extracellular matrix remodeling. However, distinct expression patterns characteristic for each pathway were also identified in cell signaling, growth, and physiology. In addition, genes with dynamic expression differences between early vs. late stages illustrated primary vs. secondary changes on MAP kinase activation in adult hearts. These results provide an overview to both short-term and long-term effects of MAP kinase activation in heart and support some common as well as unique roles for each MAP kinase cascade in the development of heart failure.

Animals↗

PubMed2005

Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor.

Macrophage death in advanced atherosclerosis promotes necrosis and plaque destabilization. A likely cause of macrophage death is accumulation of free cholesterol (FC) in the ER, leading to activation of the unfolded protein response (UPR) and C/EBP homologous protein (CHOP)-induced apoptosis. Here we show that p38 MAPK signaling is necessary for CHOP induction and apoptosis. Additionally, two other signaling pathways must cooperate with p38-CHOP to effect apoptosis. One involves the type A scavenger receptor (SRA). As evidence, FC loading by non-SRA mechanisms activates p38 and CHOP, but not apoptosis unless the SRA is engaged. The other pathway involves c-Jun NH2-terminal kinase (JNK)2, which is activated by cholesterol trafficking to the ER, but is independent of CHOP. Thus, FC-induced apoptosis requires cholesterol trafficking to the ER, which triggers p38-CHOP and JNK2, and engagement of the SRA. These findings have important implications for understanding how the UPR, MAPKs, and the SRA might conspire to cause macrophage death, lesional necrosis, and plaque destabilization in advanced atherosclerotic lesions.

Animals↗

PubMed2005

Molecular and functional signature of heart hypertrophy during pregnancy.

During pregnancy, the heart develops a reversible physiological hypertrophic growth in response to mechanical stress and increased cardiac output; however, underlying molecular mechanisms remain unknown. Here, we investigated pregnancy-related changes in heart structure, function, and gene expression of known markers of pathological hypertrophy and cell stretching in mice hearts. In late pregnancy, hearts show eccentric hypertrophy, as expected for a response to volume overload, with normal left ventricular diastolic function and a moderate reduction in systolic function. Pregnancy-related physiological heart hypertrophy does not induce expression changes of known markers of pathological hypertrophy like: alpha- and beta-myosin heavy chain, atrial natriuretic factor, phospholamban, and sarcoplasmic reticulum Ca2+-ATPase. Instead, it induces the remodeling of Kv4.3 channel and increased c-Src tyrosine kinase activity, a stretch-responsive kinase. Cardiac Kv4.3 channel gene expression was downregulated by approximately 3- to 5-fold, both at the mRNA and protein levels, and was paralleled by a reduction in transient outward K+ currents, a longer action potential and by prolongation of the QT interval. Downregulation of cardiac Kv4.3 transcripts was mimicked by estrogen treatment in ovariectomized mice, and was prevented by the estrogen receptor antagonist ICI 182,780. c-Src activity increased by approximately 2-fold in late pregnancy and after estrogen treatment. We propose that, in addition to mechanical stress, the rise of estrogen toward the end of pregnancy contributes to pregnancy-related heart hypertrophy by increased c-Src activity and that the rise of estrogen is one factor that down regulates cardiac Kv4.3 gene expression providing a molecular correlate for a longer QT interval in pregnancy.

Action Potentials↗

PubMed2005

p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes.

Adult mammalian cardiomyocytes are considered terminally differentiated and incapable of proliferation. Consequently, acutely injured mammalian hearts do not regenerate, they scar. Here, we show that adult mammalian cardiomyocytes can divide. One important mechanism used by mammalian cardiomyocytes to control cell cycle is p38 MAP kinase activity. p38 regulates expression of genes required for mitosis in cardiomyocytes, including cyclin A and cyclin B. p38 activity is inversely correlated with cardiac growth during development, and its overexpression blocks fetal cardiomyocyte proliferation. Activation of p38 in vivo by MKK3bE reduces BrdU incorporation in fetal cardiomyocytes by 17.6%. In contrast, cardiac-specific p38alpha knockout mice show a 92.3% increase in neonatal cardiomyocyte mitoses. Furthermore, inhibition of p38 in adult cardiomyocytes promotes cytokinesis. Finally, mitosis in adult cardiomyocytes is associated with transient dedifferentiation of the contractile apparatus. Our findings establish p38 as a key negative regulator of cardiomyocyte proliferation and indicate that adult cardiomyocytes can divide.

Animals↗

PubMed2005

p38 MAP kinase mediates inflammatory cytokine induction in cardiomyocytes and extracellular matrix remodeling in heart.

BACKGROUND: Increasing evidence suggests that development of heart failure involves activation of stress-response inflammatory cytokines, including tumor necrosis factor-alpha and interleukin-6. Yet, the myocyte contribution to their induction in failing hearts and the underlying regulatory mechanism in stressed myocardium remain unclear. METHODS AND RESULTS: In cultured cardiac myocytes, specific activation of stress-activated mitogen-activated protein kinase, p38, by upstream activator MKK6bE led to significant induction of tumor necrosis factor-alpha and interleukin-6 secretion, whereas treating cells with a selective p38 inhibitor (SB239068) significantly blocked the cytokine secretion from myocytes and increased their intracellular accumulation. Targeted expression of MKK6bE in transgenic hearts also resulted in a marked elevation in plasma tumor necrosis factor-alpha and interleukin-6; oral administration of SB239068 resulted in a significant reduction in their plasma levels but an increase in intracardiac accumulation of both cytokines. MKK6bE transgenic hearts developed marked interstitial fibrosis with increased matrix metalloproteinase abundance and selective induction of tissue inhibitor of matrix metalloproteinase-1; this extracellular matrix remodeling was also significantly attenuated by p38 inhibition. Along with cytokine induction and extracellular remodeling, MKK6bE transgenic animals displayed impaired hemodynamic function, whereas p38 inhibition improved the cardiac performance and prolonged the survival of the animals. CONCLUSIONS: Stress-activated p38 kinase is a critical regulator of inflammatory response in cardiomyocytes with significant contribution to pathological remodeling in stressed myocardium. Inhibition of p38 may represent a useful therapeutic avenue to ameliorate cardiac pathology and heart failure evolution.

Animals↗

PubMed2005

Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load.

Cardiac pressure load stimulates hypertrophy, often leading to chamber dilation and dysfunction. ROS contribute to this process. Here we show that uncoupling of nitric oxide synthase-3 (NOS3) plays a major role in pressure load-induced myocardial ROS and consequent chamber remodeling/hypertrophy. Chronic transverse aortic constriction (TAC; for 3 and 9 weeks) in control mice induced marked cardiac hypertrophy, dilation, and dysfunction. Mice lacking NOS3 displayed modest and concentric hypertrophy to TAC with preserved function. NOS3(-/-) TAC hearts developed less fibrosis, myocyte hypertrophy, and fetal gene re-expression (B-natriuretic peptide and alpha-skeletal actin). ROS, nitrotyrosine, and gelatinase (MMP-2 and MMP-9) zymogen activity markedly increased in control TAC, but not in NOS3(-/-) TAC, hearts. TAC induced NOS3 uncoupling in the heart, reflected by reduced NOS3 dimer and tetrahydrobiopterin (BH4), increased NOS3-dependent generation of ROS, and lowered Ca(2+)-dependent NOS activity. Cotreatment with BH4 prevented NOS3 uncoupling and inhibited ROS, resulting in concentric nondilated hypertrophy. Mice given the antioxidant tetrahydroneopterin as a control did not display changes in TAC response. Thus, pressure overload triggers NOS3 uncoupling as a prominent source of myocardial ROS that contribute to dilatory remodeling and cardiac dysfunction. Reversal of this process by BH4 suggests a potential treatment to ameliorate the pathophysiology of chronic pressure-induced hypertrophy.

Animals↗

PubMed2005

Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy.

Sustained cardiac pressure overload induces hypertrophy and pathological remodeling, frequently leading to heart failure. Genetically engineered hyperstimulation of guanosine 3',5'-cyclic monophosphate (cGMP) synthesis counters this response. Here, we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase-5A (PDE5A) inhibitor (sildenafil) suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction. Sildenafil also reverses pre-established hypertrophy induced by pressure load while restoring chamber function to normal. cGMP catabolism by PDE5A increases in pressure-loaded hearts, leading to activation of cGMP-dependent protein kinase with inhibition of PDE5A. PDE5A inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK1/2 signaling pathways). But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo, suggesting upstream targeting of these pathways. PDE5A inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling.

3',5'-Cyclic-GMP Phosphodiesterases↗