sirolimus and Hypertrophy--Left-Ventricular

Left ventricular hypertrophy (LVH) is highly prevalent in kidney transplant recipients and is associated with poor clinical outcome. Immunosuppressive agents might affect LVH behavior after kidney transplantation. This review is an appraisal of available data regarding LVH in renal transplantation and especially of studies that evaluated LVH response to treatment. In particular, the role of mammalian target of rapamycin inhibitors adopted as immunosuppressive agents in kidney transplantation is reviewed in the light of recent studies that have shown LVH regression induced by this class of medications in kidney transplant recipients with posttransplant cardiomyopathy. Larger randomized controlled trials are warranted to confirm these findings and to ascertain the impact of such LVH regression on hard endpoints in kidney transplant recipients with posttransplant cardiomyopathy.

Topics: Everolimus; Graft Rejection; Humans; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Postoperative Period; Protein Kinase Inhibitors; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

When subjected to pressure overload, the ventricular myocardium shifts from fatty acids to glucose as its main source for energy provision and frequently increases its mass. Here, we review the evidence in support of the concept that metabolic remodeling, measured as an increased myocardial glucose uptake using dynamic positron emission tomography (PET) with the glucose analogue 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG), precedes the onset of left ventricular hypertrophy (LVH) and heart failure. Consistent with this, early intervention with propranolol, which attenuates glucose uptake, prevents the maladaptive metabolic response and preserves cardiac function in vivo. We also review ex vivo studies suggesting a link between dysregulated myocardial glucose metabolism, intracellular accumulation of glucose 6-phosphate (G6P) and contractile dysfunction of the heart. G6P levels correlate with activation of mTOR (mechanistic target of rapamycin) and endoplasmic reticulum stress. This sequence of events could be prevented by pretreatment with rapamycin (mTOR inhibition) or metformin (enzyme 5'-AMP-activated protein kinase activation). In conclusion, we propose that metabolic imaging with FDG PET may provide a novel approach to guide the treatment of patients with hypertension-induced LVH.

Topics: 3-O-Methylglucose; Animals; Disease Models, Animal; Endoplasmic Reticulum Stress; Fatty Acids; Glucose-6-Phosphate; Heart Failure; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Hypoglycemic Agents; Metformin; Mice; Myocardium; Positron-Emission Tomography; Rats; Sirolimus; TOR Serine-Threonine Kinases; Ventricular Function, Left

Calcineurin inhibitor drugs (CNI) are the mainstay of modern immunosuppression in renal transplantation. However, they contribute significantly to the chronic loss of renal grafts and the high morbidity and mortality in this population due to their deleterious effects on the renal graft, cardiovascular profile and tumour pathology. Anti-mTOR drugs, sirolimus (SRL) and everolimus (EVE) are potent immunosuppressants with antiproliferative and anti-migratory capacities. These properties mean that they have a potential protective role in graft dysfunction, in renal function optimisation and the appearance of malignant tumours. Indeed, clinical trials and observational studies have demonstrated that conversion from CNI to anti-mTOR-based maintenance therapy has beneficial effects on transplant outcomes in terms of renal function, without significant increase in acute rejection rates. This review article examines the evidence of the use of anti-mTOR in the following clinical situations following renal transplantation: 1) prevention of immune dysfunction and renal function preservation in de novo renal transplantation and after early or late CNI withdrawal; 2) chronic dysfunction of the renal graft; 3) cardiovascular effects; 4) de novo post-transplant diabetes, and 5) de novo tumour pathology.

Topics: Animals; Calcineurin Inhibitors; Diabetes Mellitus, Type 2; Dyslipidemias; Everolimus; Evidence-Based Medicine; Graft Rejection; Graft vs Host Disease; Humans; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Kidney; Kidney Transplantation; Models, Animal; Multicenter Studies as Topic; Neoplasms; Postoperative Complications; Randomized Controlled Trials as Topic; Sirolimus; TOR Serine-Threonine Kinases

Left ventricular hypertrophy (LVH) contributes to elevated cardiac mortality with graft function in renal transplant recipients. Antihypertensive therapy, and especially angiotensin-converting enzyme (ACE) inhibitors, proved to be effective in regressing the LVH of renal transplant recipients, at least in part by interacting with immunosuppressive agents, thus raising the possibility that immunosuppressive therapy might affect changes in the left ventricular mass (LVM) of recipients. This review mainly focuses on the potential role of mammalian target of rapamycin (mTOR) inhibition to regress cardiac hypertrophy in both experimental models and in the clinical setting. We comment on the results of experimental studies conducted on animal models, which showed regression of cardiac hypertrophy by sirolimus (SRL). We also discuss clinical studies that show that conversion from calcineurin inhibitors to SRL is effective to achieve regression of LVH in both kidney and cardiac transplant recipients, mainly by reducing the true left ventricular wall hypertrophy.

Topics: Animals; Antihypertensive Agents; Calcineurin Inhibitors; Disease Models, Animal; Humans; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

End-stage kidney disease is frequently associated with left ventricular hypertrophy (LVH), a condition more prevalent in the elderly, that may increase mortality after renal transplantation (RTx). Previous studies suggested that mTOR inhibitors (mTORi) can improve LVH, but this has never been tested in elderly kidney transplant recipients. In this prospective randomized clinical trial, we analyzed the impact of Everolimus (EVL) on the reversal of LVH after RTx in elderly recipients (≥60 years) submitted to different immunosuppressive regimens: EVL/lowTacrolimus (EVL group, n = 53) or mycophenolate sodium/regularTacrolimus (MPS group, n = 47). Patients performed echocardiograms (Echo) up to 3 months after RTx and then annually. At baseline, mean age was 65±3 years in both groups and LVH was observed in 63.6% of patients in EVL group and in 61.8% of MPS group. Last Echo was performed at mean time of 47 and 49 months after RTx in EVL and MPS groups, respectively (P = .34). LVH regression was observed in 23.8% (EVL group) and 19% (MPS group) of patients (P = 1.00). Mean eGFR, blood pressure, and use of RAS blockers were similar between groups throughout follow-up. EVL did not improve LVH in this cohort, and this lack of benefit may be attributed to concomitant use of TAC, senescence, or both.

Topics: Aged; Everolimus; Humans; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; MTOR Inhibitors; Prospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Transplant Recipients

Although conversion from calcineurin inhibitors to mammalian target of rapamycin inhibitors proved to be effective in regressing left ventricular hypertrophy (LVH) in renal transplant recipients (RTRs) with chronic allograft dysfunction, there are currently no reports of randomized trials on this issue involving de novo RTRs administered everolimus (EVL).. This randomized, open-label, controlled trial evaluated the effect of EVL on the left ventricular mass index (LVMi) of 30 nondiabetic RTRs (21 men; age 28-65 years). Ten were allocated to EVL plus reduced-exposure cyclosporine A (CsA), and 20 to standard dose CsA. LVMi was assessed by echocardiography both at baseline and 1 year later. Blood pressure (BP), hemoglobin, serum creatinine, lipids, trough levels of immunosuppressive drugs, and daily proteinuria were also evaluated twice monthly. Antihypertensive therapy that did not include renin-angiotensin system blockers was administered to achieve BP less than or equal to 130/80 mm Hg.. Changes in BP were similar in the two groups (between group difference 1.2 ± 5.7 mm Hg, P=0.84 for systolic, and -1.5 ± 3.7, P=0.69, for diastolic BP), whereas LVMi significantly decreased in the EVL group alone (between group difference 9.2 ± 3.1 g/m(2.7), P=0.005), due to a reduction in both the interventricular septum and the left ventricular posterior wall thickness. EVL therapy together with baseline LVMi were the only significant predictors of LVH regression according to a multivariate model that explained 49% of the total LVMi variance (P=0.0015).. An immunosuppressive regimen consisting of EVL plus reduced exposure CsA proved to be effective in regressing LVH in RTRs regardless of BP, mainly by reducing left ventricular wall thickness.

Topics: Adult; Aged; Biomarkers; Blood Pressure; Chi-Square Distribution; Cyclosporine; Drug Therapy, Combination; Everolimus; Female; Humans; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Italy; Kidney Transplantation; Linear Models; Male; Middle Aged; Risk Assessment; Risk Factors; Sirolimus; Time Factors; Treatment Outcome; Ultrasonography

Left ventricular hypertrophy (LVH) after renal transplantation may be affected by immunosuppressive therapy.. Nonrandomized controlled trial evaluating the effect of sirolimus (SRL) on LVH of renal transplant recipients (RTRs).. 13 RTRs without diabetes who had received a single-kidney transplant from a deceased donor with chronic allograft dysfunction and biopsy-proven allograft nephropathy who were converted from calcineurin-inhibitor (CNI) to SRL treatment; 26 controls matched for age and year of transplantation who were not converted from CNI to SRL treatment.. Conversion from CNI to SRL therapy.. Left ventricular mass determination by using echocardiography at baseline and again 1 year later. Blood pressure (BP), hemoglobin level, serum creatinine level, uric acid level, lipid levels, trough levels of immunosuppressive drugs, and daily proteinuria were assessed at least twice monthly. Conventional antihypertensive therapy was used to achieve BP of 130/80 mm Hg or less.. The study population included 26 men and 13 women (age, 25 to 66 years). Changes in BP were similar in the 2 groups (between-group difference, -4 +/- 5 mm Hg; P = 0.5 for systolic BP; -2 +/- 3; P = 0.6 for diastolic BP), whereas left ventricular mass significantly decreased in the SRL group alone (between-group difference, 8.6 +/- 2.4 g/m(2.7); P < 0.001) because of a decrease in both the interventricular septum and left ventricular posterior wall. LVH regressed in 12 of 13 patients on SRL therapy and 10 of 26 controls (P = 0.002).. Nonrandomized design. Single-center study with small sample size.. Conversion from CNI to SRL therapy may regress LVH in RTRs regardless of BP changes, mainly by decreasing left ventricular wall thickness, thus suggesting nonhemodynamic-effect mechanisms of SRL on left ventricular mass.

Topics: Adult; Aged; Disease Progression; Dose-Response Relationship, Drug; Echocardiography; Female; Follow-Up Studies; Graft Rejection; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Sirolimus; Time Factors; Treatment Outcome; Ventricular Function, Left

Compelling evidence has described that the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Our team's previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mammalian rapamycin receptor (mTOR) signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. For that, ovariectomized (OVX) spontaneously hypertensive rats (SHR) aged 12 weeks were used to study the effects of testosterone (T 2.85 mg/kg/weekly i.m.) on blood pressure and myocardial tissue. On the basis of antihypertensive therapy (chlorthalidone 8 mg/kg/day ig), the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin (0.8 mg/kg/day vs 1.5 mg/kg/day vs 2 mg/kg/day i.p.) in OVX + estrogen (E 9.6 mg/kg/day, ig) + testosterone group was further evaluated. After testosterone intervention, the OVX female rats exhibited significant increments in the heart weight/tibial length (TL), area of cardiomyocytes and the mRNA expressions of ANP, β-myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and tissue inhibitor of metalloproteinase 1. mTOR, ribosomal protein S6 kinase (S6K1), 4E-binding protein 1 (4EBP1) and eukaryotic translation initiation factor 4E in myocardial tissue of OVX + estrogen + testosterone group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of testosterone-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive female rats with high testosterone levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate testosterone-induced cardiomyocyte hypertrophy.

Topics: Animals; Blood Pressure; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Hypertrophy, Left Ventricular; Intracellular Signaling Peptides and Proteins; MTOR Inhibitors; Myocardium; Ovariectomy; Rats, Inbred SHR; Rats, Wistar; Ribosomal Protein S6 Kinases; Signal Transduction; Sirolimus; Testosterone; TOR Serine-Threonine Kinases

Topics: Animals; Cardiotonic Agents; Drug Resistance; Free Radical Scavengers; Hypertrophy, Left Ventricular; Male; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Reperfusion Injury; Organometallic Compounds; Oxidative Stress; Reactive Nitrogen Species; Reactive Oxygen Species; Salicylates; Sirolimus

Reactive oxygen species (ROS) are elevated in the heart in response to hemodynamic and metabolic stress and promote hypertrophic signaling. ROS also mediate the formation of lipid peroxidation-derived aldehydes that may promote myocardial hypertrophy. One lipid peroxidation by-product, 4-hydroxy-trans-2-nonenal (HNE), is a reactive aldehyde that covalently modifies proteins thereby altering their function. HNE adducts directly inhibit the activity of LKB1, a serine/threonine kinase involved in regulating cellular growth in part through its interaction with the AMP-activated protein kinase (AMPK), but whether this drives myocardial growth is unclear. We tested the hypothesis that HNE promotes myocardial protein synthesis and if this effect is associated with impaired LKB1-AMPK signaling. In adult rat ventricular cardiomyocytes, exposure to HNE (10 μM for 1h) caused HNE-LKB1 adduct formation and inhibited LKB1 activity. HNE inhibited the downstream kinase AMPK, increased hypertrophic mTOR-p70S6K-RPS6 signaling, and stimulated protein synthesis by 27.1 ± 3.5%. HNE also stimulated Erk1/2 signaling, which contributed to RPS6 activation but was not required for HNE-stimulated protein synthesis. HNE-stimulated RPS6 phosphorylation was completely blocked using the mTOR inhibitor rapamycin. To evaluate if LKB1 inhibition by itself could promote the hypertrophic signaling changes observed with HNE, LKB1 was depleted in adult rat ventricular myocytes using siRNA. LKB1 knockdown did not replicate the effect of HNE on hypertrophic signaling or affect HNE-stimulated RPS6 phosphorylation. Thus, in adult cardiac myocytes HNE stimulates protein synthesis by activation of mTORC1-p70S6K-RPS6 signaling most likely mediated by direct inhibition of AMPK. Because HNE in the myocardium is commonly increased by stimuli that cause pathologic hypertrophy, these findings suggest that therapies that prevent activation of mTORC1-p70S6K-RPS6 signaling may be of therapeutic value.

Topics: Aldehydes; AMP-Activated Protein Kinases; Animals; Cells, Cultured; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Hypertrophy, Left Ventricular; Lipid Peroxidation; Male; Mechanistic Target of Rapamycin Complex 1; Multiprotein Complexes; Myocardium; Myocytes, Cardiac; Phosphorylation; Protein Biosynthesis; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Ribosomal Protein S6; Ribosomal Protein S6 Kinases, 70-kDa; RNA Interference; RNA, Small Interfering; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The heart has two major modalities of hypertrophy in response to hemodynamic loads: concentric and eccentric hypertrophy caused by pressure and volume overload (VO), respectively. However, the molecular mechanism of eccentric hypertrophy remains poorly understood. Here we demonstrate that the Akt-mammalian target of rapamycin (mTOR) axis is a pivotal regulator of eccentric hypertrophy during VO. While mTOR in the heart was activated in a left ventricular end-diastolic pressure (LVEDP)-dependent manner, mTOR inhibition suppressed eccentric hypertrophy and induced cardiac atrophy even under VO. Notably, Akt was ubiquitinated and phosphorylated in response to VO, and blocking the recruitment of Akt to the membrane completely abolished mTOR activation. Various growth factors were upregulated during VO, suggesting that these might be involved in Akt-mTOR activation. Furthermore, the rate of eccentric hypertrophy progression was proportional to mTOR activity, which allowed accurate estimation of eccentric hypertrophy by time-integration of mTOR activity. These results suggested that the Akt-mTOR axis plays a pivotal role in eccentric hypertrophy, and mTOR activity quantitatively determines the rate of eccentric hypertrophy progression. As eccentric hypertrophy is an inherent system of the heart for regulating cardiac output and LVEDP, our findings provide a new mechanistic insight into the adaptive mechanism of the heart.

Topics: Animals; Arteriovenous Fistula; Echocardiography; Heart; Hemodynamics; Hypertrophy, Left Ventricular; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Myocardium; Phosphorylation; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases; Ubiquitination; Up-Regulation

The deoxycorticosterone acetate (DOCA)-salt mouse model exhibits adverse cardiac remodeling in male mice and cardiac protection in female mice, even when blood pressure is normalized. We hypothesized that intact mammalian target of rapamycin (mTOR) signaling is necessary for cardiac protection in females. We first tested sex differences and intracellular signaling after mTOR targeting with rapamycin in wild-type mice. Radio-telemetric blood pressure was maintained at normal for 6 weeks. Rapamycin significantly reduced left ventricular hypertrophy, preserved ejection fraction, inhibited fibrosis, and maintained capillary structure in male mice. Decreased mTORC1 and increased mTORC2 activity were detected in rapamycin-treated male mice compared with vehicle controls. In contrast, female mice developed dilative left ventricular hypertrophy, cardiac fibrosis, and capillary loss similar to DOCA-salt females lacking the estrogen receptor β (ERβ(-/-)) that we described earlier. Because rapamycin downregulated ERβ in female mice, we next studied ERβ(-/-) normotensive DOCA-salt females. Vehicle-treated wild-type females maintained their high constitutive mTORC1 and mTORC2 in response to DOCA-salt. In contrast to males, both mTORCs were decreased by rapamycin, in particular mTORC2 by 60%. ERβ(-/-) DOCA-salt females showed similar mTORC1 and mTORC2 response patterns. We suggest that ERβ-dependent regulation involves sex-specific use of mTOR signaling branches. Maintenance of both mTORC1 and mTORC2 signaling seems to be essential for adaptive cardiac remodeling in females and supports a rationale for sex-specific therapeutic strategies in left ventricular hypertrophy.

Topics: Adaptation, Physiological; Animals; Blood Pressure; Capillaries; Desoxycorticosterone; Disease Models, Animal; Estrogen Receptor beta; Female; Heart; Hypertrophy, Left Ventricular; Male; Mice; Mice, Inbred C57BL; Mineralocorticoids; Sex Factors; Signal Transduction; Sirolimus; Stroke Volume; TOR Serine-Threonine Kinases

Autophagy is activated in cardiomyocytes in ischaemic heart disease, but its dynamics and functional roles remain unclear after myocardial infarction. We observed the dynamics of cardiomyocyte autophagy and examined its role during postinfarction cardiac remodelling.. Myocardial infarction was induced in mice by ligating the left coronary artery. During both the subacute and chronic stages (1 and 3 weeks postinfarction, respectively), autophagy was found to be activated in surviving cardiomyocytes, as demonstrated by the up-regulated expression of microtubule-associated protein-1 light chain 3-II (LC3-II), p62 and cathepsin D, and by electron microscopic findings. Activation of autophagy, specifically the digestion step, was prominent in cardiomyocytes 1 week postinfarction, especially in those bordering the infarct area, while the formation of autophagosomes was prominent 3 weeks postinfarction. Bafilomycin A1 (an autophagy inhibitor) significantly aggravated postinfarction cardiac dysfunction and remodelling. Cardiac hypertrophy was exacerbated in this group and was accompanied by augmented ventricular expression of atrial natriuretic peptide. In these hearts, autophagic findings (i.e. expression of LC3-II and the presence of autophagosomes) were diminished, and activation of AMP-activated protein kinase was enhanced. Treatment with rapamycin (an autophagy enhancer) brought about opposite outcomes, including mitigation of cardiac dysfunction and adverse remodelling. A combined treatment with bafilomycin A1 and rapamycin offset each effect on cardiomyocyte autophagy and cardiac remodelling in the postinfarction heart.. These findings suggest that cardiomyocyte autophagy is an innate mechanism that protects against progression of postinfarction cardiac remodelling, implying that augmenting autophagy could be a therapeutic strategy.

Topics: AMP-Activated Protein Kinases; Analysis of Variance; Animals; Atrial Natriuretic Factor; Autophagy; Blotting, Western; Cathepsin D; Disease Models, Animal; Enzyme Activation; Fluorescent Antibody Technique; Heart Ventricles; Hypertrophy, Left Ventricular; Macrolides; Mice; Microscopy, Electron; Microtubule-Associated Proteins; Myocardial Infarction; Myocytes, Cardiac; Phosphorylation; Sirolimus; Time Factors; Ventricular Function, Left; Ventricular Remodeling

LKB1 encodes a serine/threonine kinase, which functions upstream of the AMP-activated protein kinase (AMPK) superfamily. To clarify the role of LKB1 in heart, we generated and characterized cardiac myocyte-specific LKB1 knock-out (KO) mice using alpha-myosin heavy chain-Cre deletor strain. LKB1-KO mice displayed biatrial enlargement with atrial fibrillation and cardiac dysfunction at 4 weeks of age. Left ventricular hypertrophy was observed in LKB1-KO mice at 12 weeks but not 4 weeks of age. Collagen I and III mRNA expression was elevated in atria at 4 weeks, and atrial fibrosis was seen at 12 weeks. LKB1-KO mice displayed cardiac dysfunction and atrial fibrillation and died within 6 months of age. Indicative of a prohypertrophic environment, the phosphorylation of AMPK and eEF2 was reduced, whereas mammalian target of rapamycin (mTOR) phosphorylation and p70S6 kinase phosphorylation were increased in both the atria and ventricles of LKB1-deficient mice. Consistent with vascular endothelial growth factor mRNA and protein levels being significantly reduced in LKB1-KO mice, these mice also exhibited a reduction in capillary density of both atria and ventricles. In cultured cardiac myocytes, LKB1 silencing induced hypertrophy, which was ameliorated by the expression of a constitutively active form AMPK or by treatment with the inhibitor of mTOR, rapamycin. These findings indicate that LKB1 signaling in cardiac myocytes is essential for normal development of the atria and ventricles. Cardiac hypertrophy and dysfunction in LKB1-deficient hearts are associated with alterations in AMPK and mTOR/p70S6 kinase/eEF2 signaling and with a reduction in vascular endothelial growth factor expression and vessel rarefaction.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Antibiotics, Antineoplastic; Atrial Fibrillation; Carrier Proteins; Collagen Type I; Collagen Type II; Fibrosis; Gene Expression Regulation; Heart Atria; Hypertrophy, Left Ventricular; Mice; Mice, Knockout; Myocardium; Organ Specificity; Peptide Elongation Factor 2; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor); Protein Kinases; Protein Serine-Threonine Kinases; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

The cellular mechanisms underlying cardiac hypertrophy may result from changes in cardiac myocyte growth and differentiation. We tested whether sirolimus, an immunosuppressive agent that inhibits mTOR, a protein that regulates cell division and differentiation, might modify cardiac hypertrophy after cardiac transplantation.. Fifty-eight cardiac transplant recipients were withdrawn from treatment with calcineurin inhibitors (CNIs) and treated with sirolimus. Eighty-three control subjects were maintained on CNIs. After 12 months, left ventricular (LV) mass decreased from 196.15 +/- 48.28 to 182.21 +/- 43.56 g (P = 0.05) and LV mass index from 99.25 +/- 20.08 to 93.82 +/- 20.22 g/m(2) (P = 0.031) in sirolimus-treated subjects but did not change in controls. The left atrial volume index of sirolimus-treated subjects decreased from 52.44 +/- 17.22 to 48.40 +/- 15.14 cc/m(2) (P = 0.008) and increased from 52.07 +/- 19.45 to 57.03 +/- 19.93 cc/m(2) (P = 0.0012) in controls. The difference between the groups was independent of blood pressure. The number of cells in myocardial biopsies positive for p27Kip1, a protein induced by mTOR inhibition, increased in sirolimus-treated subjects (P = 0.0005) and did not change in controls (P = 0.54) suggesting sirolimus acted directly on myocardium.. Sirolimus may inhibit adverse ventricular remodelling resulting in cardiac hypertrophy and have potential in the treatment of conditions in which severe hypertrophy compromises cardiac function.

Topics: Calcineurin; Female; Heart Transplantation; Humans; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Male; Middle Aged; Myocytes, Cardiac; Protein Kinases; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Ultrasonography; Ventricular Function, Left

Topics: Heart Transplantation; Humans; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Kidney; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases

Inhibition of established left ventricular hypertrophy (LVH) and fibrosis may bring clinical benefits by reducing cardiac morbidity and mortality. The mammalian target of rapamycin, mTOR, is known to play a critical role in determining cell and organ size. We investigated whether mTOR inhibition can inhibit the chronic pressure-overload-induced LVH and fibrosis.. Male FVB/N mice underwent transverse aortic constriction (TAC) for 5 weeks to allow for establishment of LVH, followed by treatment with the mTOR inhibitor, Rapamune (2 mg/kg per day, gavage), for 4 weeks. Echocardiography was used to monitor changes in LVH and function. Haemodynamic, morphometric, histological and molecular analyses were conducted.. Inhibition of mTOR by Rapamune was confirmed by a suppression of activated phosphorylation of ribosomal S6 protein and eukaryotic translation initiation factor-4E due to pressure overload. Despite a comparable degree of pressure overload between the vehicle- or Rapamune-treated TAC groups, Rapamune treatment for 4 weeks attenuated TAC-induced LVH by 46%, estimated by LV weight or myocyte size, and LV fractional shortening was also preserved versus vehicle-treated control (39 +/- 1 versus 32 +/- 2%, P < 0.05). Inhibition of established LVH by Rapamune was associated with a 38% reduction in collagen content. Moreover, altered gene expression due to pressure overload was largely restored.. Despite sustained pressure overload, inhibition of mTOR by a 4-week period of Rapamune treatment attenuates chronically established LVH and cardiac fibrosis with preserved contractile function.

Topics: Analysis of Variance; Animals; Atrial Natriuretic Factor; Blood Pressure; Chronic Disease; Disease Models, Animal; Down-Regulation; Eukaryotic Initiation Factor-4E; Fibrosis; Heart Rate; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Male; Mice; Mitogen-Activated Protein Kinase 3; Myosin Heavy Chains; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Kinases; Ribosomal Protein S6; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Signal Transduction; Sirolimus; STAT3 Transcription Factor; Stroke Volume; TOR Serine-Threonine Kinases

Rapamycin inhibits p70 S6 kinase (p70(S6K)) activity and hypertrophy of cultured neonatal rat cardiac myocytes. The purpose of the present study was to determine whether rapamycin inhibits left ventricular (LV) hypertrophy in intact rats and whether it alters cardiac gene expression.. 300 g rats were subjected to aortic constriction (AC) or sham-operation (SH) and studied 2 and 3 days after surgery. Beginning 1 day prior to surgery, rats were injected with rapamycin (1.5 mg/kg, i.p.) or carboxymethylcellulose vehicle (V), yielding 4 groups (SH-V, SH-R, AC-V, AC-R). Total RNA was extracted for determination of mRNA levels by Northern blotting.. LV dry weight/body weight ratios were 0.43 +/- 0.04 (mean +/- SE) for SH-V, 0.46 +/- 0.02 for SH-R, 0.56 +/- 0.02 for AC-V, and 0.53 +/- 0.03 for AC-R. R inhibited cardiac hypertrophy induced by pressure overload (ANOVA; p < 0.05). Rapamycin had no effect on the expression of atrial natriuretic factor mRNA, but increased the levels of beta-myosin heavy chain mRNA 6-fold in hearts of SH-R and AC-R compared to SH-V. Rapamycin also increased the expression of alpha-myosin heavy chain mRNA in SH-R by 3-fold compared with SH-V, but had no effect on the AC-R group.. The data suggest that an intact mTOR signaling pathway is required for rapid hypertrophic growth of the heart in vivo. Moreover, the data suggest a novel link between the mTOR/p70(S6K) signal transduction pathway and pretranslational control of myosin gene expression in the heart.

Topics: Animals; Aorta; Blotting, Northern; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Activation; Heart Ventricles; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Male; Myosin Heavy Chains; Promoter Regions, Genetic; Protein Kinases; Rats; Rats, Sprague-Dawley; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Messenger; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Up-Regulation; Vasoconstriction