Biomedical subjects

Harvey S Hahn

Publications and source records attributed to Harvey S Hahn.

17 recordsLinked to original sources

PubMed2006

STAT-3 activation is necessary for ischemic preconditioning in hypertrophied myocardium.

The JAK-STAT pathway is activated in the early and late phases of ischemic preconditioning (IPC) in normal myocardium. The role of this pathway and the efficacy of IPC in hypertrophied hearts remain largely unknown. We hypothesized that phosphorylated STAT-3 (pSTAT-3) is necessary for effective IPC in pressure-overload hypertrophy. Male Sprague-Dawley rats 8 wk after thoracic aortic constriction (TAC) or sham operation underwent echocardiography and Langendorff perfusion. Randomized hearts were subjected to 30 min of global ischemia and 120 min of reperfusion with or without IPC in the presence or absence of the JAK-2 inhibitor AG-490 (AG). Functional recovery and STAT activation were assessed. TAC rats had a 31% increase in left ventricular mass (1,347 +/- 58 vs. 1,028 +/- 43 mg, TAC vs. sham, P < 0.001), increased anterior and posterior wall thickness but no difference in ejection fraction compared with sham-operated rats. In TAC, IPC improved end-reperfusion maximum first derivative of developed pressure (+dP/dt(max); 4,648 +/- 309 vs. 2,737 +/- 343 mmHg/s, IPC vs. non-IPC, P < 0.05) and minimum -dP/dt (-dP/dt(min); -2,239 +/- 205 vs. -1,215 +/- 149 mmHg/s, IPC vs. non-IPC, P < 0.05). IPC increased nuclear pSTAT-1 and pSTAT-3 in sham-operated rats but only pSTAT-3 in TAC. AG in TAC significantly attenuated +dP/dt(max) (4,648 +/- 309 vs. 3,241 +/- 420 mmHg/s, IPC vs. IPC + AG, P < 0.05) and -dP/dt(min) (-2,239 +/- 205 vs. -1,323 +/- 85 mmHg/s, IPC vs. IPC + AG, P < 0.05) and decreased only nuclear pSTAT-3. In myocardial hypertrophy, JAK-STAT signaling is important in IPC and exhibits a pattern of STAT activation distinct from nonhypertrophied myocardium. Limiting STAT-3 activation attenuates the efficacy of IPC in hypertrophy.

Animals↗

PubMed2006

The presence of Lys27 instead of Asn27 in human phospholamban promotes sarcoplasmic reticulum Ca2+-ATPase superinhibition and cardiac remodeling.

BACKGROUND: Phospholamban (PLN) is an inhibitor of the Ca2+ affinity of sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA2). The amino acid sequence of PLN is highly conserved, and although all species contain asparagine (Asn), human PLN is unique in containing lysine (Lys) at amino acid 27. METHODS AND RESULTS: Human PLN was introduced in the null background. Expression of human PLN, at similar levels to mouse wild-type PLN, resulted in significant decreases in the affinity of SERCA2 for Ca2+, attributed to unique spatial conformation of this PLN form and increases in its monomeric active unit compared with mouse PLN. The increased inhibition by human PLN was associated with attenuated cardiac contractility in the intact-animal, organ, and cardiomyocyte levels and with depressed calcium kinetics. These inhibitory effects could not be fully reversed even on maximal isoproterenol stimulation. There were no alterations in the expression levels of SERCA2, calsequestrin, ryanodine receptor, and FKBP12, although the sodium/calcium exchanger and the L-type Ca2+ channel expression levels were upregulated. The depressed function resulted in increased heart/body weight ratios and phosphorylation levels of Akt, p38, and Erk1/2. CONCLUSIONS: Human PLN may play a more inhibitory role than that of other species in Ca2+ cycling. Expression of human PLN in the mouse is compensated by alterations in Ca2+-handling proteins and cardiac remodeling in an effort to normalize cardiac contractility. Thus, the unique amino acid sequence of human PLN may be critical in maintaining a high cardiac reserve, which is of paramount importance in the regulation of human cardiac function.

Amino Acid Sequence↗

PubMed2005

Cardiac myosin-binding protein-C phosphorylation and cardiac function.

The role of cardiac myosin binding protein-C (cMyBP-C) phosphorylation in cardiac physiology or pathophysiology is unclear. To investigate the status of cMyBP-C phosphorylation in vivo, we determined its phosphorylation state in stressed and unstressed mouse hearts. cMyBP-C phosphorylation is significantly decreased during the development of heart failure or pathologic hypertrophy. We then generated transgenic (TG) mice in which the phosphorylation sites of cMyBP-C were changed to nonphosphorylatable alanines (MyBP-C(AllP-)). A TG line showing &40% replacement with MyBP-C(AllP-) showed no changes in morbidity or mortality but displayed depressed cardiac contractility, altered sarcomeric structure and upregulation of transcripts associated with a hypertrophic response. To explore the effect of complete replacement of endogenous cMyBP-C with MyBP-C(AllP-), the mice were bred into the MyBP-C(t/t) background, in which less than 10% of normal levels of a truncated MyBP-C are present. Although MyBP-C(AllP-) was incorporated into the sarcomere and expressed at normal levels, the mutant protein could not rescue the MyBP-C(t/t) phenotype. The mice developed significant cardiac hypertrophy with myofibrillar disarray and fibrosis, similar to what was observed in the MyBP-C(t/t) animals. In contrast, when the MyBP-C(t/t) mice were bred to a TG line expressing normal MyBP-C (MyBP-CWT), the MyBP-C(t/t) phenotype was rescued. These data suggest that cMyBP-C phosphorylation is essential for normal cardiac function.

Animals↗

PubMed2005

Proapoptotic effects of caspase-1/interleukin-converting enzyme dominate in myocardial ischemia.

Caspase-1/interleukin-converting enzyme (ICE) is a cysteine protease traditionally considered to have importance as an inflammatory mediator, but not as an apoptotic effector. Because of the dual functions of this caspase, the pathophysiological impact of its reported upregulation in hypertrophy and heart failure is not known. Here, the consequences of increased myocardial expression of procaspase-1 were examined on the normal and ischemically injured heart. In unstressed mouse hearts with a 30-fold increase in procaspase-1 content, unprocessed procaspase-1 was well tolerated, without detectable pathology. Cardiomyocyte processing and activation of caspase-1 and caspase-3 occurred after administration of endotoxin or with transient myocardial ischemia. In post-ischemic hearts, procaspase-1 overexpression was associated with strikingly increased cardiac myocyte apoptosis in the peri- and noninfarct regions and with 50% larger myocardial infarctions. Tissue culture studies revealed that procaspase-1 processing/activation is stimulated by hypoxia, and that caspase-1 acts in synergy with hypoxia to stimulate caspase-3 mediated apoptosis without activating upstream caspases. These data demonstrate that the proapoptotic effects of caspase-1 can significantly impact the myocardial response to ischemia and suggest that conditions in which procaspase-1 in the heart is increased may predispose to apoptotic myocardial injury under conditions of physiological stress.

Animals↗

PubMed2005

Murine echocardiography: a practical approach for phenotyping genetically manipulated and surgically modeled mice.

There have now been literally hundreds of genetically manipulated mouse models developed during the past decade of cardiac research. Echocardiography is considered an extremely important tool to noninvasively assess and serially follow the phenotype of genetically and surgically altered mice. This review describes in detail the technical considerations, various routinely used methods to assess cardiac function, and some emerging techniques in the assessment of cardiac function in experimental mouse models of cardiac disease.

Animals↗

PubMed2005

Sarcoplasmic reticulum adenosine triphosphatase overexpression in the L-type Ca2+ channel mouse results in cardiomyopathy and Ca2+ -induced arrhythmogenesis.

BACKGROUND: Overexpression of the L-type voltage-dependent calcium channel alpha(1C)-subunit (L-VDCC OE) in transgenic mice results in adaptive hypertrophy followed by a maladaptive phase associated with a decrease in sarcoplasmic reticulum adenosine triphosphatase (SERCA)2a expression at 8 to 10 months of age. Overexpressing SERCA to manipulate calcium (Ca(2+)) cycling and prevent pathologic phenotypes in some models of heart failure has been proven to be a promising genetic strategy. OBJECTIVE: In this study we investigated whether genetic manipulation that increases Ca(2+) uptake into the sarcoplasmic reticulum by overexpressing SERCA1a (skeletal muscle specific) into the L-VDCC OE background could restore or further deteriorate Ca(2+) cycling, contractile dysfunction, and electrical remodeling in the heart failure phenotype. RESULTS: We found that the survival rate of L-VDCC OE/SERCA1a OE double transgenic mice decreased by 50%. L-VDCC OE/SERCA1a OE mice displayed an accelerated phenotype of severe dilation of both ventricles associated with deteriorated left ventricular function. Voltage clamp experiments revealed enhanced increased inward Ca(2+) current density and decreased the transient outward potassium current. Action potential duration in double transgenic ventricular myocytes was prolonged, and isoproterenol induced early after depolarization. These mice demonstrated a high incidence of spontaneous left ventricular arrhythmia. Expression of the proarrhythmic signaling protein Ca(2+)/calmodulin-dependent kinase II (CaMKII) was increased while connexin43 expression was decreased, defining an important putative mechanism in the electrophysiologic disturbances and mortality. CONCLUSIONS: Despite previous reports of improved cardiac function in heart failure models after SERCA intervention, our results advocate the need to elucidate the involvement of augmented Ca(2+) cycling in arrhythmogenesis.

Action Potentials↗

PubMed2004

Physiological growth synergizes with pathological genes in experimental cardiomyopathy.

Hundreds of signaling molecules have been assigned critical roles in the pathogenesis of myocardial hypertrophy and heart failure based on cardiac phenotypes from alpha-myosin heavy chain-directed overexpression mice. Because permanent ventricular transgene expression in this system begins during a period of rapid physiological neonatal growth, resulting phenotypes are the combined consequences of transgene effects and normal trophic influences. We used temporally-defined forced gene expression to investigate synergy between postnatal physiological cardiac growth and two functionally divergent cardiomyopathic genes. Phenotype development was compared various times after neonatal (age 2 to 3 days) and adult (age 8 weeks) expression. Proapoptotic Nix caused ventricular dilation and severe contractile depression in neonates, but not adults. Myocardial apoptosis was minimal in adults, but was widespread in neonates, until it spontaneously resolved in adulthood. Unlike normal postnatal cardiac growth, concurrent left ventricular pressure overload hypertrophy did not synergize with Nix expression to cause cardiomyopathy or myocardial apoptosis. Prohypertrophic Galphaq likewise caused eccentric hypertrophy, systolic dysfunction, and pathological gene expression in neonates, but not adults. Thus, normal postnatal cardiac growth can be an essential cofactor in development of genetic cardiomyopathies, and may confound the interpretation of conventional alpha-MHC transgenic phenotypes.

Amino Acid Sequence↗

PubMed2004

Regulation of cardiac contractility by Rab4-modulated beta2-adrenergic receptor recycling.

Catecholaminergic activation of myocardial beta-adrenergic receptors (betaAR) is the principle mechanism regulating cardiac function. Agonists desensitize betaAR through G protein-coupled receptor kinase-mediated uncoupling and beta-arrestin-mediated internalization. Although inhibition of myocardial G protein-coupled receptor kinase-2 enhances cardiac function and reverses heart failure, pathophysiological effects of modulated betaAR internalization/recycling are unknown. We used mutation and transgenic expression of Rab4, which regulates vesicular transport of heptahelical receptors to plasma membranes, to interrogate in vivo betaAR trafficking and cardiac function. Expression of constitutively active Rab4 Q72L had no effects on cardiac structure or function, but dominant inhibitor Rab4 S27N impaired responsiveness to endogenous and exogenous catecholamines. To relate betaAR trafficking to diminished cardiac function, Rab4 mutant mice were crossbred with mice overexpressing human beta2AR. In unstimulated beta2AR overexpressors, beta2AR localized to heavier endosomes and translocated to lighter, caveolin-rich fractions after isoproterenol stimulation. Coexpression of beta2AR with activated Rab4 Q72L caused loss of receptors from heavier endosomes while retaining normal inotropy. In contrast, coexpression of beta2AR with inhibitory Rab4 S27N mimicked isoproterenol-induced receptor redistribution to caveolae, with diminished cardiac inotropy. Rab4 inhibition alone prevented resensitization after isoproterenol-induced in vivo adrenergic desensitization. Confocal and ultrastructural analyses revealed bizarre vesicular structures and abnormal accumulation of beta2AR in the sarcoplasm and subsarcollema of Rab4 S27N, but not Q72L, mice. These data provide evidence for constant bidirectional sarcollemal-vesicular betaAR trafficking in the in vivo heart and show that Rab4-mediated recycling of internalized betaAR is necessary for normal cardiac catecholamine responsiveness and resensitization after agonist exposure.

Adrenergic beta-2 Receptor Agonists↗

PubMed2004

Evolution of the mdx mouse cardiomyopathy: physiological and morphological findings.

Heart failure is a major cause of death in boys with Duchenne muscular dystrophy. In order to determine if the cardiac function of the mdx mouse is similarly disturbed, we performed murine echocardiograms and left heart catheterization studies, along with morphometric analysis of cardiac fibrosis. Serial echocardiograms in mdx mice revealed the evolution from normal cardiac function in young mice to a dilated cardiomyopathy in adult mice. Very old mdx mice exhibited a widespread but patchy increase in ventricular wall fibrosis. These results show that the mdx cardiac function is more impaired than was previously thought and shares important clinical features with the cardiomyopathy of Duchenne muscular dystrophy.

Aging↗

PubMed2004

Genetic factors in cardiac hypertrophy.

Cardiac hypertrophy is an adaptive response to any cardiac insult or stress that increases hemodynamic load. Cardiac hypertrophy can exist in a state of compensation or progress to a decompensated state (i.e., heart failure) over time. It has been established through transgenic overexpression and gene ablation studies that multiple signaling pathways are involved in the induction of hypertrophy as well as its decompensation. This article reviews the role of G alpha q in the development of pressure overload hypertrophy and discusses the relationships between G alpha q and beta-adrenergic receptors, RGS proteins, and the proapoptotic factor, Nix/Bnip3L.

Apoptosis↗

PubMed2003

Protein kinase Calpha negatively regulates systolic and diastolic function in pathological hypertrophy.

The protein kinase C (PKC) family is implicated in cardiac hypertrophy, contractile failure, and beta-adrenergic receptor (betaAR) dysfunction. Herein, we describe the effects of gain- and loss-of-PKCalpha function using transgenic expression of conventional PKC isoform translocation modifiers. In contrast to previously studied PKC isoforms, activation of PKCalpha failed to induce cardiac hypertrophy, but instead caused betaAR insensitivity and ventricular dysfunction. PKCalpha inhibition had opposite effects. Because PKCalpha is upregulated in human and experimental cardiac hypertrophy and failure, its effects were also assessed in the context of the Galphaq overexpression model (in which PKCalpha is transcriptionally upregulated). Normalization (inhibition) of PKCalpha activity in Galpha(q) hearts improved systolic and diastolic function, whereas further activation of PKCalpha caused a lethal restrictive cardiomyopathy with marked interstitial fibrosis. These results define pathological roles for PKCalpha as a negative regulator of ventricular systolic and diastolic function.

Adrenergic beta-Agonists↗

PubMed2003

Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure.

Catecholamines stimulate cardiac contractility through beta(1)-adrenergic receptors (beta(1)-ARs), which in humans are polymorphic at amino acid residue 389 (Arg/Gly). We used cardiac-targeted transgenesis in a mouse model to delineate mechanisms accounting for the association of Arg389 with human heart failure phenotypes. Hearts from young Arg389 mice had enhanced receptor function and contractility compared with Gly389 hearts. Older Arg389 mice displayed a phenotypic switch, with decreased beta-agonist signaling to adenylyl cyclase and decreased cardiac contractility compared with Gly 389 hearts. Arg389 hearts had abnormal expression of fetal and hypertrophy genes and calcium-cycling proteins, decreased adenylyl cyclase and G alpha(s) expression, and fibrosis with heart failure This phenotype was recapitulated in homozygous, end-stage, failing human hearts. In addition, hemodynamic responses to beta-receptor blockade were greater in Arg389 mice, and homozygosity for Arg389 was associated with improvement in ventricular function during carvedilol treatment in heart failure patients. Thus the human Arg389 variant predisposes to heart failure by instigating hyperactive signaling programs leading to depressed receptor coupling and ventricular dysfunction, and influences the therapeutic response to beta-receptor blockade.

Adrenergic beta-Antagonists↗

PubMed2003

Additive protection of the ischemic heart ex vivo by combined treatment with delta-protein kinase C inhibitor and epsilon-protein kinase C activator.

BACKGROUND: Protein kinase C (PKC) plays a major role in cardioprotection from ischemia/reperfusion injury. Using an HIV-1 Tat protein-derived peptide to mediate rapid and efficient transmembrane delivery of peptide regulators of PKC translocation and function, we examined the cardioprotective effect of selective delta-PKC inhibitor (deltaV1-1) and epsilon-PKC activator (psi(epsilon)RACK) peptides for ischemia/reperfusion damage in isolated perfused rat hearts. Furthermore, we examined the protective effects of these PKC isozymes in isolated perfused hearts subjected to ischemia/reperfusion damage using transgenic mice expressing these peptides specifically in their cardiomyocytes. METHODS AND RESULTS: In isolated perfused rat hearts, administration of deltaV1-1 but not psi(epsilon)RACK during reperfusion improved cardiac function and decreased creatine phosphokinase release. In contrast, pretreatment with psi(epsilon)RACK but not deltaV1-1, followed by a 10-minute washout before ischemia/reperfusion, also improved cardiac function and decreased creatine phosphokinase release. Furthermore, administration of psi(epsilon)RACK before ischemia followed by deltaV1-1 during reperfusion only conferred greater cardioprotective effects than that obtained by each peptide treatment alone. Both the delta-PKC inhibitor and epsilon-PKC activator conferred cardioprotection against ischemia/reperfusion injury in transgenic mice expressing these peptides in the heart, and coexpression of both peptides conferred greater cardioprotective effects than that obtained by the expression of each peptide alone. CONCLUSIONS: delta-PKC inhibitor prevents reperfusion injury, and epsilon-PKC activator mimics ischemic preconditioning. Furthermore, treatment with both peptides confers additive cardioprotective effects. Therefore, these peptides mediate cardioprotection by regulating ischemia/reperfusion damage at distinct time points.

Amino Acid Sequence↗

PubMed2003

Electrical remodeling in hearts from a calcium-dependent mouse model of hypertrophy and failure: complex nature of K+ current changes and action potential duration.

OBJECTIVES: This study was designed to identify possible electrical remodeling (ER) in transgenic (Tg) mice with over-expressed L-type Ca(2+) channels. Transient outward K(+) current (I(to)) and action potential duration (APD) were studied in 2-, 4-, 8-, and 9- to 12-month-old mice to determine linkage to ventricular remodeling (VR), ER, and heart failure (HF). BACKGROUND: Prolongation of APD and reduction in current density of I(to) are thought to be hallmarks of VR and HF. Mechanisms are not understood. METHODS: Patch-clamp, perfused hearts, echocardiography, and Western blots were employed using 2-, 4-, 8-, and 9- to 12-month-old Tg mice. RESULTS: Transgenic mice developed slow VR statistically manifesting at four months and continuing through death at 12 to 14 months, despite a slight up-regulation of I(to). A slight decrease or no change in APD was observed up to eight months; however, at 9 to 12 months, a small increase in APD was detected. Early afterdepolarizations were observed after application of 4-aminopyridine in Tg mice. No change was detected in protein of Kv4.3 and Kv4.2 up to eight months. At 9 to 12 months, Tg mice showed a slight decrease (41.4 +/- 6.9%, p < 0.05) in Kv4.2, consistent with a decrease in I(to). Surprisingly, Kv1.4 (the "fetal" K(+)-channel form) was up-regulated, and restitution of I(to) was slowed. Echocardiography revealed cardiac enlargement with impaired chamber function in hearts that were taken from the older animals. CONCLUSIONS: Contrary to accepted dogma, APD and I(to) in a mouse model of hypertrophy and HF are not hallmarks of pathophysiology. We suggest that [Ca(2+)](i) (i.e., [Ca(2+)] concentration) is the primary factor in triggering cardiac enlargement and arrhythmogenesis.

Action Potentials↗

PubMed2003

Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy.

Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca(2+) cycling. Normalization of Ca(2+) cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Galphaq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-C(MUT)) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca(2+) transients and enhanced unloaded fractional shortening with no change in SR Ca(2+) pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Galphaq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Galphaq pathway or MyBP-C mutations.

Animals↗

PubMed2003

Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human.

In human disease and experimental animal models, depressed Ca(2+) handling in failing cardiomyocytes is widely attributed to impaired sarcoplasmic reticulum (SR) function. In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN mutations in humans are unknown. Here, a T116G point mutation, substituting a termination codon for Leu-39 (L39stop), was identified in two families with hereditary heart failure. The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27. An over 50% reduction in PLN mRNA and no detectable PLN protein were noted in one explanted heart. The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293 cells and adult rat cardiomyocytes showed no PLN inhibition of SR Ca(2+)-ATPase and the virtual absence of stable PLN expression; where PLN was expressed, it was misrouted to the cytosol or plasma membrane. These findings describe a naturally-occurring loss-of-function human PLN mutation (PLN null). In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy.

Animals↗

PubMed2002

Ischemic protection and myofibrillar cardiomyopathy: dose-dependent effects of in vivo deltaPKC inhibition.

To delineate the in vivo cardiac functions requiring normal delta protein kinase C (PKC) activity, we pursued loss-of-function through transgenic expression of a deltaPKC-specific translocation inhibitor protein fragment, deltaV1, in mouse hearts. Initial results using the mouse alpha-myosin heavy chain (alphaMHC) promoter resulted in a lethal heart failure phenotype. Viable deltaV1 mice were therefore obtained using novel attenuated mutant alphaMHC promoters lacking one or the other thyroid response element (TRE-1 and -2). In transgenic mouse hearts, deltaV1 decorated cytoskeletal elements and inhibited ischemia-induced deltaPKC translocation. At high levels, deltaV1 expression was uniformly lethal, with depressed cardiac contractile function, increased expression of fetal cardiac genes, and formation of intracardiomyocyte protein aggregates. Ultrastructural and immunoconfocal analyses of these aggregates revealed focal cytoskeletal disruptions and localized concentrations of desmin and alphaB-crystallin. In individual cardiomyocytes, cytoskeletal abnormalities correlated with impaired contractile function. Whereas desmin and alphaB-crystallin protein were increased approximately 4-fold in deltaV1 hearts, combined overexpression of these proteins at these levels was not sufficient to cause any detectable cardiac pathology. At low levels, deltaV1 expression conferred striking resistance to postischemic dysfunction, with no measurable effects on basal cardiac structure, function, or gene expression. Intermediate expression of deltaV1 conferred modest basal contractile depression with less ischemic protection, associated with abnormal cardiac gene expression, and a histological picture of infrequent cardiomyocyte cytoskeletal deformities. These results validate an approach of deltaPKC inhibition to protect against myocardial ischemia, but indicate that there is a threshold level of deltaPKC activation that is necessary to maintain normal cardiomyocyte cytoskeletal integrity.

Animals↗