By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence supporting this notion is based on several findings: (i) a highly selective nonpeptide MC4R agonist augments erectile activity initiated by electrical stimulation of the cavernous nerve in wild-type but not Mc4r-null mice; (ii) copulatory behavior is enhanced by administration of a selective MC4R agonist and is diminished in mice lacking Mc4r; (iii) reverse transcription (RT)-PCR and non-PCR based methods demonstrate MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and (iv) in situ hybridization of glans tissue from the human and rat penis reveal MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicate the MC4R in the modulation of penile erectile function and provide evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. Our results provide a basis for the existence of MC4R-controlled neuronal pathways that control sexual function.O ur understanding of the physiology and anatomy of erectile function has advanced considerably in recent years (1-4). Penile erection is a highly coordinated reflex that is subject to modulation at many levels of the neuraxis. Relaxation of smooth muscle fibers of erectile tissue and concomitant dilatation of the arterial supply in the penis produce penile erection. Activation of neurons in the sacral spinal cord triggers activity in the pelvic nerve and, subsequently, the cavernous nerve, which can lead to the release of mediators of vasorelaxation, including nitric oxide. These mediators modulate cyclic nucleotide levels resulting in Ca 2ϩ sequestration and relaxation of smooth muscle fibers of the corpora cavernosa and corpus spongiosum in the shaft of the penis to produce arterial dilatation, engorgement of the penis with blood, and tumescence. Erections can be triggered either by peripheral (tactile) or by central (visual, olfactory, auditory, or imaginative cues) activation of somatic pathways and, as such, are influenced by tonic and phasic activity in the lumbosacral spinal cord and the brain.Five melanocortin heterotrimeric GTP-binding protein (G protein)-coupled receptors have been identified as expressed in different tissues (5, 6). The functional role of each of these five melanocortin receptors is being defined. Rodent and human genetic and pharmacological evidence indicates that activation of melanocortin 4 receptor (MC4R) results in a lean phenotype, whereas inactivation of the MC4R results in obesity (7-10). Recent studies have demonstrated that MTII, a cyclic analogue of ␣-mel...

Background-Probiotics are extensively used to promote gastrointestinal health, and emerging evidence suggests that their beneficial properties can extend beyond the local environment of the gut. Here, we determined whether oral probiotic administration can alter the progression of postinfarction heart failure. Methods and Results-Rats were subjected to 6 weeks of sustained coronary artery occlusion and administered the probiotic Lactobacillus rhamnosus GR-1 or placebo in the drinking water ad libitum. Culture and 16s rRNA sequencing showed no evidence of GR-1 colonization or a significant shift in the composition of the cecal microbiome. However, animals administered GR-1 exhibited a significant attenuation of left ventricular hypertrophy based on tissue weight assessment and gene expression of atrial natriuretic peptide. Moreover, these animals demonstrated improved hemodynamic parameters reflecting both improved systolic and diastolic left ventricular function. Serial echocardiography revealed significantly improved left ventricular parameters throughout the 6-week follow-up period including a marked preservation of left ventricular ejection fraction and fractional shortening. Beneficial effects of GR-1 were still evident in those animals in which GR-1 was withdrawn at 4 weeks, suggesting persistence of the GR-1 effects after cessation of therapy. Investigation of mechanisms showed a significant increase in the leptin:adiponectin plasma concentration ratio in rats subjected to coronary ligation, which was abrogated by GR-1. Metabonomic analysis showed differences between sham control and coronary artery ligated hearts particularly with respect to preservation of myocardial taurine levels. Conclusions-The study suggests that probiotics offer promise as a potential therapy for the attenuation of heart failure.(Circ Heart Fail. 2014;7:491-499.)

No abstract

The recently-identified fat mass and obesity-associated (FTO) protein is associated with various physiological functions including energy and body weight regulation. Ubiquitously expressed, FTO was identified in heart homogenates although its function is unknown. We studied whether FTO is specifically expressed within the cardiac myocyte and its potential role pertaining to the hypertrophic effect of the adipokine leptin. Most experiments were performed using cultured neonatal rat cardiomyocytes which showed nuclei-specific FTO expression. Leptin significantly increased FTO expression which was associated with myocyte hypertrophy although both events were abrogated by FTO knockdown with siRNA. Administration of a leptin receptor antibody to either normal or obese rats significant reduced myocardial FTO protein expression. Responses in cardiomyocytes were accompanied by JAK2/STAT3 activation whereas JAK2/STAT3 inhibition abolished these effects. Expression of the cut-like homeobox 1(CUX1) transcriptional factor was significantly increased by leptin although this was restricted to the cathepsin L-dependent, proteolytically-derived shorter p110CUX1 isoform whereas the longer p200CUX1 protein was not significantly affected. Cathepsin L expression and activity were both significantly increased by leptin whereas a cathepsin L peptide inhibitor or siRNA specific for CUX1 completely prevented the leptin-induced increase in FTO expression. The cathepsin L peptide inhibitor or siRNA-induced knockdown of either CUX1 or FTO abrogated the hypertrophic response to leptin. Two other pro-hypertrophic factors, endothelin-1 or angiotensin II had no effect on FTO expression and FTO knockdown did not alter the hypertrophic response to either agent. This study demonstrates leptin-induced FTO upregulation in cardiomyocytes via JAK2/STAT3- dependent CUX1 upregulation and suggests an FTO regulatory function of leptin. It also demonstrates for the first time a functional role of FTO in the cardiomyocyte.

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

A BTI improved child self-efficacy, parent self-efficacy, and parent outcome expectations, which warrants a larger RCT to examine long-term changes to these behavioral constructs and ACS.

Background-A major challenge in the treatment of heart failure is the ability to reverse already-established myocardial remodeling and ventricular dysfunction, with few available pharmacological agents prescribed for the management of heart failure having demonstrated successful reversal of the remodeling and hypertrophic processes. North American ginseng (Panax quinquefolius) has previously been shown to effectively prevent cardiomyocyte hypertrophy and heart failure. Here, we determined whether North American ginseng can reverse established cardiomyocyte hypertrophy in cultured myocytes as well as hypertrophy and left ventricular dysfunction in experimental heart failure secondary to coronary artery occlusion. Methods and Results-Ginseng was administered in drinking water (0.9 g/L) ad libitum to rats after 4 weeks of sustained coronary artery ligation when heart failure was established or to angiotensin II-(100 nmol/L), endothelin-1-(10 nmol/L), or phenylephrine-(10 µmol/L) induced hypertrophic cultured neonatal ventricular cardiomyocytes. Echocardiographic and catheter-based measurements of hemodynamic parameters 4 weeks after starting ginseng treatment (8 weeks postinfarction) revealed nearly complete reversibility of systolic and diastolic abnormalities. Similarly, ginseng administration to hypertrophic cardiomyocytes resulted in a complete reversal to a normal phenotype after 24 hours as determined by cell surface area and expression of molecular markers. The effects of ginseng both in vivo and in cultured cardiomyocytes were associated with reversal of calcineurin activation and reduced nuclear translocation of the transcription factor NFAT3 (nuclear factor of activated T cells 3) in cultured myocytes. Moreover, the beneficial effect of ginseng was associated with normalization in the gene expression of profibrotic markers, including collagen (I and III) and fibronectin. Conclusions-This study demonstrates a marked ability of ginseng to reverse cardiac hypertrophy, myocardial remodeling, and heart failure, which was associated with and likely mediated by reversal of calcineurin activation. Ginseng may offer a potentially effective approach to reverse the myocardial remodeling and heart failure processes, particularly in combination with other treatment modalities.

Cluster of differentiation 73 (CD73) is an ecto-5' nucleotidase which catalyzes the conversion of AMP to adenosine. One of the many functions of adenosine is to suppress the activity of tissue nonspecific alkaline phosphatase (TNAP), an enzyme important in regulating intracellular calcification. Since myocardial calcification is associated with various cardiac disease states, we studied the individual roles and crosstalk between CD73 and TNAP in regulating myocyte responses to the α1 adrenoceptor agonist phenylephrine in terms of calcification and hypertrophy. Cultured neonatal rat cardiomyocytes were treated with 10 µM phenylephrine for 24 h in the absence or presence of the stable adenosine analog 2-chloro-adenosine, the TNAP inhibitor tetramisole or the CD73 inhibitor α,β-methylene ADP. Phenylephrine produced marked hypertrophy as evidenced by significant increases in myocyte surface area and ANP gene expression, as well as calcification determined by Alizarin Red S staining. These responses were associated with reduced CD73 gene and protein expression and CD73 activity. Conversely, TNAP expression and activity were significantly increased although both were suppressed by 2-chloro-adenosine. CD73 inhibition alone significantly reduced myocyte-derived adenosine levels by >50 %, and directly induced hypertrophy and calcification in the absence of phenylephrine. These responses and those to phenylephrine were abrogated by TNAP inhibition. We conclude that TNAP contributes to the hypertrophic effect of phenylephrine, as well as its ability to produce cardiomyocyte calcification. These responses are minimized by CD73-dependent endogenously produced adenosine.