ß-Blockers promote angiogenesis in the mouse aortic ring assay.

Recent results indicate that the reduction of ß-adrenergic signaling impairs angiogenesis under ischemic conditions. Because angiogenesis may occur in the absence of ischemia, it remains to be determined whether and how ß-adrenergic signaling regulates angiogenesis, which develops under normoxic conditions. The effect of ß-adrenergic ligands on angiogenesis was investigated using 3-dimensional cultures of mouse aortic rings embedded in collagen type I, in which luminized microvessels develop in response to vascular endothelial growth factor (VEGF). Under normoxic conditions, both isoproterenol, a ß-adrenergic receptor (ß-AR) agonist, and forskolin, an adenylate cyclase activator, were unable to influence aortic microvessel sprouting. On the contrary, treatment with propranolol, a ß-AR antagonist, caused an approximately 70% increase in VEGF-mediated microvessel sprouting. This effect was abolished in rings from both double ß-AR and ß1-AR knockout mice, but not in rings from ß2-AR knockout mice. Significant increases in microvessel sprouting were also observed when mouse aortic rings from C57BL/6 mice were treated with the ß1-AR-selective antagonists metoprolol and bisoprolol or with the ß2-AR-selective antagonist ICI 118,551. Conversely, carvedilol, a nonselective ß-AR antagonist, was unable to affect aortic sprouting. These findings suggest that some ß-blockers display proangiogenic activity through a mechanism that is independent of their ability to antagonize catecholamine action. The present results also identify a new function for ß-AR signaling as a facilitator for VEGF-mediated angiogenesis and have implications for understanding the mechanisms that regulate angiogenic responses under normoxic conditions.

MLC1 trafficking and membrane expression in astrocytes: role of caveolin-1 and phosphorylation.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare congenital leukodystrophy caused by mutations in the MLC1 gene that encodes a membrane protein of unknown function. In the brain MLC1 protein is mainly expressed in astrocyte end-feet, localizes in lipid rafts and associates with the dystrophin glycoprotein complex (DGC). Using pull-down and co-fractionation assays in cultured human and rat astrocytes, we show here that MLC1 intracellular domains pull-down the DGC proteins syntrophin, dystrobrevin, Kir4.1 and caveolin-1, the structural protein of caveolae, thereby supporting a role for DGC and caveolar structures in MLC1 function. By immunostaining and subcellular fractionation of cultured rat or human astrocytes treated with agents modulating caveolin-mediated trafficking, we demonstrate that MLC1 is also expressed in intracellular vesicles and endoplasmic reticulum and undergoes caveolae/raft-mediated endocytosis. Inhibition of endocytosis, cholesterol lowering and protein kinases A- and C-mediated MLC1 phosphorylation favour the expression of membrane-associated MLC1. Because pathological mutations prevent MLC1 membrane expression, the identification of substances regulating MLC1 intracellular trafficking is potentially relevant for the therapy of MLC.

Association between epicardial fat thickness and cognitive function in elderly. A preliminary study.

BACKGROUND: Recent studies suggested that the visceral fat could exert a predictive role in the pathogenesis of dementia. The aims of the present study were to evaluate: i) possible differences between groups with different epicardial adipose tissue (EAT) thickness on the included variables; ii) the possible predictive role of the EAT levels on cognitive functioning. METHODS: 65 community-dwelling subjects were enrolled and divided into two groups: EAT < 7 mm (n = 36); EAT > 7 mm (n = 29). The metabolic profile was assessed through the evaluation of the biochemical parameters whereas the EAT thickness was measured through the transthoracic echocardiography. The Mini Mental State Examination (MMSE) was also administered. RESULTS: The two EAT groups reported several significant differences, included on the MMSE scores. The multiple linear regression analysis showed that the EAT thickness levels and the hypertension had a predictive effect on the MMSE scores. CONCLUSIONS: These preliminary findings support the association between EAT thickness levels and cognitive impairment.

Maternal exposure to low levels of corticosterone during lactation protects the adult offspring against ischemic brain damage.

A growing body of evidence underscores the importance of early life events as predictors of health in adulthood. Abnormalities in maternal care or other forms of early postnatal stress induce long-term changes in behavior and influence the vulnerability to illnesses throughout life. Some of these changes may be produced by the activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is invariably associated with stress. We used a model in which neonate rats are fed by mothers drinking water supplemented with 0.2 mg/ml corticosterone, the main glucocorticoid hormone in rodents. Plasma corticosterone levels increased in the dams to an extent similar to that induced by a mild stress. Corticosterone-treated dams also showed an increase in maternal care. Remarkably, adult rats that had been nursed by corticosterone-treated mothers were protected against neuronal damage and cognitive impairment produced by transient global brain ischemia. Neuroprotection was associated with a reduced HPA response to ischemia and was primarily decreased when corticosterone was injected at a dose that eliminated any difference in endogenous corticosterone levels between rats raised by mothers supplemented with corticosterone and their matched controls. These data suggest that an increased maternal care protects the offspring against ischemic neuronal damage and that at least a component of neuroprotection is mediated by a reduced response of the HPA axis to ischemia.

cAMP-mediated beta-adrenergic signaling negatively regulates Gq-coupled receptor-mediated fetal gene response in cardiomyocytes.

The treatment with beta-blockers causes an enhancement of the norepinephrine-induced fetal gene response in cultured cardiomyocytes. Here, we tested whether the activation of cAMP-mediated beta-adrenergic signaling antagonizes alpha(1)-adrenergic receptor (AR)-mediated fetal gene response. To address this question, the fetal gene program, of which atrial natriuretic peptide (ANP) and the beta-isoform of myosin heavy chain are classical members, was induced by phenylephrine (PE), an alpha(1)-AR agonist. In cultured neonatal rat cardiomyocytes, we found that stimulation of beta-ARs with isoproterenol, a beta-AR agonist, inhibited the fetal gene expression induced by PE. Similar results were also observed when cardiomyocytes were treated with forskolin (FSK), a direct activator of adenylyl cyclase, or 8-CPT-6-Phe-cAMP, a selective activator of protein kinase A (PKA). Conversely, the PE-induced fetal gene expression was further upregulated by H89, a selective PKA inhibitor. To evaluate whether these results could be generalized to Gq-mediated signaling and not specifically to alpha(1)-ARs, cardiomyocytes were treated with prostaglandin F(2)alpha, another Gq-coupled receptor agonist, which is able to promote fetal gene expression. This treatment caused an increase of both ANP mRNA and protein levels, which was almost completely abolished by FSK treatment. The capability of beta-adrenergic signaling to regulate the fetal gene expression was also evaluated in vivo conditions by using beta1- and beta2-AR double knockout mice, in which the predominant cardiac beta-AR subtypes are lacking, or by administering isoproterenol (ISO), a beta-AR agonist, at a subpressor dose. A significant increase of the fetal gene expression was found in beta(1)- and beta(2)-AR gene deficient mice. Conversely, we found that ANP, beta-MHC and skACT mRNA levels were significantly decreased in ISO-treated hearts. Collectively, these data indicate that cAMP-mediated beta-adrenergic signaling negatively regulates Gq cascade activation-induced fetal gene expression in cultured cardiomyocytes and that this inhibitory regulation is already operative in the mouse heart under physiological conditions.

c-Flip overexpression reduces cardiac hypertrophy in response to pressure overload.

OBJECTIVE: Activation of Fas signaling has been associated with the development of cardiomyocyte hypertrophy. In the present study, we investigated the effects of increased expression of c-Flip, a natural modulator of Fas receptor signaling, in a mouse model of cardiac growth response to pressure overload. METHODS: A transgenic mouse overexpressing c-Flip in the heart was generated in FVB/N strain. Echocardiographic, hemodynamic, histological and molecular analyses were carried out under basal conditions and after transverse aortic constriction (TAC)-induced pressure overload. RESULTS: Overexpression of c-Flip in ventricular heart tissue was functionally silent under basal conditions affecting neither cardiac morphology nor basal cardiac function. Transgenic mice were then subjected to pressure overload by TAC procedure. Under such conditions, c-Flip transgenic mice showed normal left ventricular function with a significantly reduced left ventricular hypertrophy compared with wild-type mice and reduced induction of the cardiac "fetal" gene programme. Further, analysis of intracellular signaling pathways indicated that c-Flip overexpression reduced phosphorylation of both the glycogen synthase kinase 3beta (GSK3 beta) and Akt as compared with controls. Finally, the reduction of the TAC-induced hypertrophy was not accompanied by significant apoptosis increase. CONCLUSION: Altogether, these findings indicate c-Flip as a key regulator of the cardiac response to ventricular pressure overload.

Propranolol promotes Egr1 gene expression in cardiomyocytes via beta-adrenoceptors.

Recent research has revealed that propranolol, a beta-adrenoceptor antagonist, causes extracellular signal-regulated kinase (ERK) cascade activation, nuclear translocation of phospho-ERK and increased transcriptional activity in cultured cell lines. Given the importance of beta-adrenoceptor antagonists in the treatment of heart failure, we evaluated the capability of propranolol of promoting the ERK-dependent gene expression at the cardiomyocyte level. To this end, the gene expression of the early growth response factor 1 (Egr1), a well-recognized indicator of nuclear extracellular signal-regulated kinase 1/2 (ERK1/2) activation, was assessed by quantitative real-time RT-PCR in vivo as well as in vitro experiments. Propranolol, administered at the dose of 10 mg/kg/day in C57BL/6 mice, caused a approximately 19-fold increase of Egr1 mRNA expression in left ventricular myocardium along with a approximately 2.1-fold increase of Egr1 protein expression. Isoproterenol, a nonselective beta-adrenoceptor agonist, also increased Egr1 mRNA and protein expression but to a lesser degree. Remarkably, isoproterenol administration was associated with the development of cardiac hypertrophy, whereas propranolol-treated mice showed a completely normal cardiac morphology. The effect of propranolol on Egr1 mRNA expression was abrogated in mice lacking beta(1)- and beta(2)-adrenoceptors indicating that propranolol increases Egr1 mRNA expression in a beta-adrenoceptor-dependent manner. The role of beta-adrenoceptors was further confirmed by showing that propranolol was able to increase Egr1 mRNA and protein levels in cultured neonatal cardiomyocytes. Collectively, these results indicate that propranolol promotes Egr1 gene expression in cardiomyocytes via beta-adrenoceptors with a mechanism which is independent of its ability to antagonize the effects of catecholamines. It is also suggested that cardiomyocyte growth and Egr1 gene overexpression are not obligate processes.

Association between serum vitamin D and metabolic syndrome in middle-aged and older adults and role of supplementation therapy with vitamin D.

OBJECTIVES: To evaluate i) the correlation between vitamin D (vit. D) serum concentrations and metabolic syndrome (MetS); ii) the efficacy of 6 months supplementation therapy with vit. D. METHOD: 200 patients were enrolled. Blood analyses and anthropometric measurements were carried out. Patients with hypovitaminosis D received an oral supplement therapy. RESULTS: 81% of the sample shows vit. D levels < 30 ng/mL. Rate of MetS was significantly higher in vit. D deficiency group than in vit D insufficiency (p = 0.009) and sufficiency (p = 0.002) groups. Vit. D shows a significant negative correlation with both waist circumference (WC) (ρ - 0.202 p = 0.004) and glycaemia values (FBG) (ρ -0.185 p = 0.009). After the supplementation therapy in a group of 60 subjects a significant increase in vit. D levels (p = 0.001) and a significant reduction in WC values (p = 0.001) were observed. CONCLUSIONS: MetS, WC and FBG appeared to be associated vit. D status and it is well-known that central obesity, with the inflammatory alterations thereto correlated that determine insulin resistance, can be considered the "primum movens" for the development of MetS.

Pressure overload causes cardiac hypertrophy in beta1-adrenergic and beta2-adrenergic receptor double knockout mice.

OBJECTIVE: Cardiac hypertrophy arises as an adaptive response to increased afterload. Studies in knockout mice have shown that catecholamines, but not alpha1-adrenergic receptors, are necessary for such an adaptation to occur. However, whether beta-adrenergic receptors are critical for the development of cardiac hypertrophy in response to pressure overload is not known at this time. METHODS AND RESULTS: Pressure overload was induced by transverse aortic banding in beta1-adrenergic and beta2-adrenergic receptor double knockout (DbetaKO) mice, in which the predominant cardiac beta-adrenergic receptor subtypes are lacking. Chronic pressure overload for 4 weeks induced cardiac hypertrophy in both DbetaKO and wild-type mice. There were no significant differences between banded mice in left ventricular weight to body weight ratio, in the left ventricular wall thickness, in the cardiomyocyte size or in the expression levels of the load-sensitive cardiac genes such as ANF and beta-MHC. Additionally, the left ventricular systolic pressure, an index of afterload, and cardiac contractility, evaluated as dp/dtmax, the maximal slope of systolic pressure increment, and Ees, end-systolic elastance, were increased at a similar level in both wild-type and DbetaKO banded mice, and were significantly greater than in sham controls. CONCLUSION: Despite chronic activation of the cardiac beta-adrenergic system being sufficient to induce a pathological hypertrophy, we show that beta1-adrenergic and beta2-adrenergic receptors are not an obligatory component of the signaling pathway that links the increased afterload to the development of cardiac hypertrophy.

Efficacy and safety of spinning exercise in middle-aged and older adults with metabolic syndrome: randomized control trial.

BACKGROUND: Few studies have been conducted to investigate the effects of spinning exercise on cardio-vascular weal. AIM: To assess whether a 6 months spinning training, combined with proper diet, is more effective than standard training programs and diet alone in improving metabolic abnormalities in middle-aged and older adults. DESIGN: Randomized clinical trial. SETTING: Rehabilitation Unit of our Department. POPULATION: Patients with Metabolic Syndrome (MetS) according to the National Cholesterol Education Program Adult Treatment Panel III diagnostic criteria. METHODS: Patients were randomly assigned to receive treatment with diet (group A, n = 10), with diet and general gymnastics program (group B, n = 10), with diet and spinning physical training program (group C, n = 10). RESULTS: During the study period we observed a significant reduction in blood pressure (group C: systolic blood pressure p = 0.03; diastolic blood pressure p = 0.004 / group B: systolic blood pressure p = 0.001), in lipid profile (group B: plasma total cholesterol p = 0.001; triglycerides p = 0.001 / group C: plasma total cholesterol p = 0.04); in fasting blood glucose (group B: p = 0.01; group C: p = 0.008); in Homeostatic Model Assessment of Insulin Resistance (group B: p = 0.01; group C: p = 0.001); in waist circumference (group C: p = 0.005; group A: p = 0.02; group B: p = 0.04). No patients reported adverse events during follow-up. CONCLUSION: Our results confirm the effectiveness of spinning training combined with diet in the management of MetS. CLINICAL REHABILITATION IMPACT: The findings provide a preliminary evidence to support that spinning training may represent a useful and safe intervention also in middle-aged and older adults geriatric with multiple CV risk factors.

Na+/H+ exchange inhibition attenuates left ventricular remodeling and preserves systolic function in pressure-overloaded hearts.

Cardiac hypertrophy is a homeostatic response to elevated afterload. Na+/H+ exchanger (NHE) inhibition reduces the hypertrophic response in animal models of left ventricular hypertrophy (LVH) and myocardial infarction. We examined the effect of chronic treatment with cariporide, a selective inhibitor of Na+/H+ exchanger isoform 1 (NHE-1), on left ventricular (LV) systolic and diastolic function under pressure overload conditions. Male CD-1 mice were randomized to receive either a control diet or an identical diet supplemented with 6000 p.p.m. of cariporide. Cardiac pressure overload was induced by thoracic aortic banding. LV dimension and systolic and diastolic function were assessed in sham and banded mice by echocardiography and cardiac catheterization 2 and 5 weeks after surgery. Histological analysis was also performed. After 2 weeks of pressure overload, the vehicle-treated banded mice (Veh-Bd) had enhanced normalized LV weight (about +50%) and normal chamber size and function, whereas cariporide-treated banded mice (Car-Bd) showed a preserved contractility and systolic function despite a marked attenuation of LVH. Diastolic function did not differ significantly among groups. After 5 weeks, the Veh-Bd developed LV chamber enlargement and systolic dysfunction as evidenced by a 16% increase in LV end-diastolic diameter, a 36% decrease in myocardial contractility, and a 26% reduction in percent fractional shortening. In contrast, Car-Bd showed an attenuated increase in LV mass, normal chamber size, and a maintained systolic function. A distinct histological feature was that in banded mice, cariporide attenuated the development of cardiomyocyte hypertrophy but not the attendant myocardial fibrosis. In conclusion, the results of the present study indicate that (i) the hypertrophic response to pressure overload is dependent on NHE-1 activity, and (ii) at the 5-week stage, banding-induced deterioration of LV performance is prevented by NHE-1 inhibition.British Journal of Pharmacology (2004) 141, 526-532. doi:10.1038/sj.bjp.0705631

Video-assisted orotracheal intubation in mice.

Orotracheal intubation in mice is a complicated technique because of the peculiar oropharyngeal anatomy and the difficulty in visualizing the laryngis aditus. Here we report a new and simple method for rapid endotracheal intubation by using a small bore, straight fibre-optic arthroscope. Under endoscope-assisted visualization of the laryngis aditus, a polyethylene cannula, inserted on a guide-wire in order to facilitate the introduction of the tip across the vocal cords, was advanced in the trachea. The success rate of intubation was 100%. We were also able to re-intubate the mice 4 and 8 weeks later without any major complications. We conclude that this method can be easily and safely used for studies where controlled pulmonary ventilation is necessary.

Iron excretion in iron dextran-overloaded mice.

BACKGROUND: Iron homeostasis in humans is tightly regulated by mechanisms aimed to conserve iron for reutilisation, with a negligible role played by excretory mechanisms. In a previous study we found that mice have an astonishing ability to tolerate very high doses of parenterally administered iron dextran. Whether this ability is linked to the existence of an excretory pathway remains to be ascertained. MATERIALS AND METHODS: Iron overload was generated by intraperitoneal injections of iron dextran (1 g/kg) administered once a week for 8 weeks in two different mouse strains (C57bl/6 and B6D2F1). Urinary and faecal iron excretion was assessed by inductively coupling plasma-mass spectrometry, whereas cardiac and liver architecture was evaluated by echocardiography and histological methods. For both strains, 24-hour faeces and urine samples were collected and iron concentration was determined on days 0, 1 and 2 after iron administration. RESULTS: In iron-overloaded C57bl/6 mice, the faecal iron concentration increased by 218% and 157% on days 1 and 2, respectively (p<0.01). The iron excreted represented a loss of 14% of total iron administered. Similar but smaller changes was also found in B6D2F1 mice. Conversely, we found no significant changes in the concentration of iron in the urine in either of the strains of mice. In both strains, histological examination showed accumulation of iron in the liver and heart which tended to decrease over time. CONCLUSIONS: This study indicates that mice have a mechanism for removal of excess body iron and provides insights into the possible mechanisms of excretion.

The C57BL/6 genetic background confers cardioprotection in iron-overloaded mice.

BACKGROUND: Chronic transfusion therapy causes a progressive iron overload that damages many organs including the heart. Recent evidence suggests that L-type calcium channels play an important role in iron uptake by cardiomyocytes under conditions of iron overload. Given that beta-adrenergic stimulation significantly enhances L-type calcium current, we hypothesised that beta-adrenergic blocking drugs could reduce the deleterious effects of iron overload on the heart. METHODS: Iron overload was generated by intraperitoneal injections of iron dextran (1g/kg) administered once a week for 8 weeks in male C57bl/6 mice, while propranolol was administered in drinking water at the dose of 40 mg/kg/day. Cardiac function and ventricular remodelling were evaluated by echocardiography and histological methods. RESULTS: As compared to placebo, iron injection caused cardiac iron deposition. Surprisingly, despite iron overload, myocardial function and ventricular geometry in the iron-treated mice resulted unchanged as compared to those in the placebo-treated mice. Administration of propranolol increased cardiac performance in iron-overloaded mice. Specifically, as compared to the values in the iron-overloaded group, in iron-overloaded animals treated with propranolol left ventricular fractional shortening increased (from 31.6% to 44.2%, P =0.01) whereas left ventricular end-diastolic diameter decreased (from 4.1 ± 0.1 mm to 3.5 ± 0.1 mm, P =0.03). Propranolol did not alter cardiac systolic function or left ventricular sizes in the placebo group. CONCLUSIONS: These results demonstrate that C57bl/6 mice are resistant to iron overload-induced myocardial injury and that treatment with propranolol is able to increase cardiac performance in iron-overloaded mice. However, since C57bl/6 mice were resistant to iron-induced injury, it remains to be evaluated further whether propranolol could prevent iron-overload cardiomyopathy.

Hormonal regulation of ß-myosin heavy chain expression in the mouse left ventricle.

We investigated the influence of sex hormones on the expression of α- and ß-cardiac myosin heavy chain isoforms (α-MHC and ß-MHC) in C57bl/6 mice of both sexes under physiological and pathological conditions. In the left ventricles (LVs) of fertile female mice, ß-MHC expression was tenfold higher compared with the age-matched males, whereas no difference was found in α-MHC expression. These differences disappeared after ovariectomy or in immature mice. We also found a sex-related difference in expression of ß-adrenoceptors (ß1-AR), as mRNA levels of this gene were 40% lower in fertile females compared with males of the same age but did not differ in prepubertal or ovariectomized animals. Interestingly, the deletion of both ß1- and ß2-ARs abolished sex difference of ß-MHC expression, as mRNA levels in the LVs of knockout males were increased and reached values comparable to those of knockout females. Moreover, the ß1-AR antagonist metoprolol induced about a threefold increase in ß-MHC expression in adult male mice. The capability of gender to regulate ß-MHC expression was also evaluated in the presence of hemodynamic overload. Thoracic aortic coarctation (TAC) produced cardiac hypertrophy along with a 12-fold increase in ß-MHC and a 50% decrease in ß1-AR expression in males but not in females, thus abolishing the gender difference observed in sham animals for such genes. By contrast, TAC did not change ß2-AR expression. In conclusion, our results show that the expression of ß-MHC and ß1-AR in the LVs undergo gender-related and correlated changes under both physiological and pathological conditions and suggest a role of ß1-AR-mediated signaling.

Signaling pathway-focused gene expression profiling in pressure overloaded hearts.

The ß-blocker propranolol displays antihypertrophic and antifibrotic properties in the heart subjected to pressure overload. Yet the underlying mechanisms responsible for these important effects remain to be completely understood. The purpose of this study was to determine signaling pathway-focused gene expression profile associated with the antihypertrophic action of propranolol in pressure overloaded hearts. To address this question, a focused real-time PCR array was used to screen left ventricular RNA expression of 84 gene transcripts representative of 18 different signaling pathways in C57BL/6 mice subjected to transverse aortic constriction (TAC) or sham surgery. On the surgery day, mice received either propranolol (80 mg/kg/day) or vehicle for 14 days. TAC caused a 49% increase in the left ventricular weight-to-body weight (LVW/BW) ratio without changing gene expression. Propranolol blunted LVW/BW ratio increase by approximately 50% while causing about a 3-fold increase in the expression of two genes, namely Brca1 and Cdkn2a, belonging to the TGF-beta and estrogen pathways, respectively. In conclusion, after 2 weeks of pressure overload, TAC hearts show a gene expression profile superimposable to that of sham hearts. Conversely, propranolol treatment is associated with an increased expression of genes which negatively regulate cell cycle progression. It remains to be established whether a mechanistic link between gene expression changes and the antihypertrophic action of propranolol occurs.

Propranolol enhances cell cycle-related gene expression in pressure overloaded hearts.

BACKGROUND AND PURPOSE: Cell cycle regulators are regarded as essential for cardiomyocyte hypertrophic growth. Given that the ß-adrenoceptor antagonist propranolol blunts cardiomyocyte hypertrophic growth, we determined whether propranolol alters the expression of cell cycle-related genes in mouse hearts subjected to pressure overload. EXPERIMENTAL APPROACH: Pressure overload was induced by transverse aortic constriction (TAC), whereas the expression levels of 84 cell cycle-related genes were assayed by real-time PCR. Propranolol (80 mg·kg(-1) ·day(-1) ) was administered in drinking water for 14 days. KEY RESULTS: Two weeks after surgery, TAC caused a 46% increase in the left ventricular weight-to-body weight (LVW/BW) ratio but no significant changes in cell cycle gene expression. Propranolol, at plasma concentrations ranging from 10 to 140 ng·mL(-1) , blunted the LVW/BW ratio increase in TAC mice, while significantly increasing expression of 10 cell cycle genes including mitotic cyclins and proliferative markers such as Ki67. This increase in cell cycle gene expression was paralleled by a significant increase in the number of Ki67-positive non-cardiomyocyte cells as revealed by immunohistochemistry and confocal microscopy. ß-Adrenoceptor signalling was critical for cell cycle gene expression changes, as genetic deletion of ß-adrenoceptors also caused a significant increase in cyclins and Ki67 in pressure overloaded hearts. Finally, we found that metoprolol, a ß(1) -adrenoceptor antagonist, failed to enhance cell cycle gene expression in TAC mice. CONCLUSIONS AND IMPLICATIONS: Propranolol treatment enhances cell cycle-related gene expression in pressure overloaded hearts by increasing the number of cycling non-cardiomyocyte cells. These changes seem to occur via ß(2) -adrenoceptor-mediated mechanisms.