Acute myocardial infarction (MI) due to coronary artery occlusion is accompanied by a pathological remodeling response that includes hypertrophic cardiac growth and fibrosis, which impair cardiac contractility. Previously, we showed that cardiac hypertrophy and heart failure are accompanied by characteristic changes in the expression of a collection of specific microRNAs (miRNAs), which act as negative regulators of gene expression. Here, we show that MI in mice and humans also results in the dysregulation of specific miRNAs, which are similar to but distinct from those involved in hypertrophy and heart failure. Among the MI-regulated miRNAs are members of the miR-29 family, which are downregulated in the region of the heart adjacent to the infarct. The miR-29 family targets a cadre of mRNAs that encode proteins involved in fibrosis, including multiple collagens, fibrillins, and elastin. Thus, down-regulation of miR-29 would be predicted to derepress the expression of these mRNAs and enhance the fibrotic response. Indeed, down-regulation of miR-29 with anti-miRs in vitro and in vivo induces the expression of collagens, whereas over-expression of miR-29 in fibroblasts reduces collagen expression. We conclude that miR-29 acts as a regulator of cardiac fibrosis and represents a potential therapeutic target for tissue fibrosis in general.

The calcium͞calmodulin-dependent protein phosphatase calcineurin stimulates cardiac hypertrophy in response to numerous stimuli. Calcineurin activity is suppressed by association with modulatory calcineurin-interacting protein (MCIP)1͞DSCR1, which is up-regulated by calcineurin signaling and has been proposed to function in a negative feedback loop to modulate calcineurin activity. To investigate the involvement of MCIP1 in cardiac hypertrophy in vivo, we generated MCIP1 null mice and subjected them to a variety of stress stimuli that induce cardiac hypertrophy. In the absence of stress, MCIP1 ؊/؊ animals exhibited no overt phenotype. However, the lack of MCIP1 exacerbated the hypertrophic response to activated calcineurin expressed from a musclespecific transgene, consistent with a role of MCIP1 as a negative regulator of calcineurin signaling. Paradoxically, however, cardiac hypertrophy in response to pressure overload or chronic adrenergic stimulation was blunted in MCIP1 ؊/؊ mice. These findings suggest that MCIP1 can facilitate or suppress cardiac calcineurin signaling depending on the nature of the hypertrophic stimulus. These opposing roles of MCIP have important implications for therapeutic strategies to regulate cardiac hypertrophy through modulation of calcineurin-MCIP activity.

Background-In heart failure, exercise elicits excessive increases in mean arterial pressure (MAP) and heart rate (HR).Using a novel rat model, we previously demonstrated that this exaggerated cardiovascular responsiveness is mediated by an overactive exercise pressor reflex (EPR). Although we previously determined that abnormalities in the group IV afferent neuron population (associated with the metabolic component of the reflex) initiate the development of the exaggerated EPR in heart failure, these fibers do not mediate the enhanced circulatory responses to exercise. Therefore, we hypothesized that the augmentation in EPR activity is primarily mediated by the mechanically sensitive component of the reflex (mediated predominately by activation of group III afferent fibers). Methods and Results-Male Sprague-Dawley rats were divided into 3 groups: sham (control), dilated cardiomyopathic (DCM), and neonatal capsaicin-treated animals (NNCAP, group IV afferent fibers ablated). Activation of the EPR by electrically induced static muscle contraction of the hindlimb resulted in larger increases in MAP and HR in DCM and NNCAP compared with sham animals. In all groups, administration of gadolinium (a selective blocker of mechanically sensitive receptors) within the hindlimb attenuated the MAP and HR responses to contraction. However, the magnitude of this reduction was greater in DCM and NNCAP compared with sham animals. Conclusions-From these data, we conclude that the muscle mechanoreflex mediates the exaggerated EPR that develops in heart failure. Moreover, these findings suggest that mechanoreflex overactivity in heart failure may be a compensatory response to functional alterations in group IV fibers. Given these findings, the muscle mechanoreflex may serve as a novel target in the treatment of the abnormal circulatory responses to exercise in heart failure. (Circulation. 2005;112: 2293-2300.)

The physiologic function of the progressive hyperleptinemia of diet-induced obesity is unknown. However, that lipotoxicity in nonadipose tissues of congenitally unleptinized obese rodents is far greater than in hyperleptinemic diet-induced obesity rodents has suggested an antilipotoxic role. To test this hypothesis, mice with severe lipotoxic cardiomyopathy, induced transgenically by cardiomyocyte-specific overexpression of the acyl CoA synthase (ACS) gene, were made hyperleptinemic by treatment with recombinant adenovirus containing the leptin cDNA. Normoleptinemic control ACS-transgenic mice developed severe dilated cardiomyopathy with thickened left ventricular walls and profound impairment of systolic function on echocardiogram; histologically, there was severe myofiber disorganization and interstitial fibrosis, with intracytoplasmic lipid vacuoles identifiable by electron microscope. By contrast, the hearts of hyperleptinemic ACS-transgenic mice appeared normal, with normal echocardiograms and cardiac triglyceride (TG) contents. Their lower myocardial TG content was ascribed primarily to profound lowering of plasma TG and free fatty acids; free fatty acids were 17% of normal at 8 weeks. Additionally, enhanced myocardial AMP-activated protein kinase phosphorylation may have increased fatty acid oxidation, thereby contributing to the lowering of lipid stores. We conclude that obesity-level hyperleptinemia protects the heart from lipotoxicity.leptin ͉ SIRT1 ͉ apoptosis ͉ AMP-activated protein kinase ͉ triglycerides

Naseem RH, Meeson AP, DiMaio JM, White MD, Kallhoff J, Humphries C, Goetsch SC, De Windt LJ, Williams MA, Garry MG, Garry DJ. Reparative myocardial mechanisms in adult C57BL/6 and MRL mice following injury. Physiol Genomics 30: 44 -52, 2007. First published February 27, 2007 doi:10.1152/physiolgenomics.00070.2006.-Previous studies have suggested that the heart may be capable of limited repair and regeneration in response to a focal injury, while other studies indicate that the mammalian heart has no regenerative capacity. To further explore this issue, we performed a series of superficial and transmural myocardial injuries in C57BL/6 and MRL/MpJ adult mice. At defined time intervals following the respective injury (days 3, 14, 30 and 60), we examined cardiac function using echocardiography, morphology, fluorescence-activated cell sorting for 5-bromo-2-deoxyuridine-positive cells and molecular signature using microarray analysis. We observed restoration of myocardial function in the superficial MRL cryoinjured heart and significantly less collagen deposition compared with the injured hearts of C57BL/6 mice. Following a severe transmural myocardial injury, the MRL mouse has increased survival and decreased ventricular remodeling compared with the C57BL/6 mouse but without evidence of complete regeneration. The cytoprotective program observed in the severely injured MRL heart is in part due to increased cellular proliferation, increased vasculogenesis, and decreased apoptosis that limits the extension of the injury. We conclude that MRL injured hearts have evidence of myocardial regeneration, in response to superficial injury, but the stabilized left ventricular function and improved survival observed in the MRL mouse following severe injury is not associated with complete myocardial regeneration. myocardial regeneration; cytoprotection; progenitor cells; echocardiography; TUNEL assay; transcriptome analysis AMPHIBIANS AND TELEOST FISH have a remarkable myocardial regenerative capacity following injury (5,6,33). Following the amputation of the ventricular apex in zebrafish, a well-orchestrated molecular and cellular response results in complete myocardial regeneration and an absence of scar formation (33). Studies undertaken in these metazoan models suggest a dynamic balance exists between the fibroproliferative response that produces scar and the regenerative response that produces functional, contractile tissue (6, 33).Adult mammalian tissues typically have a progenitor or stem cell population that function in the maintenance and regeneration of the tissue in which they reside (8,11,38). Bone marrow, skin, liver, skeletal muscle and brain are several examples of adult tissues that harbor somatic progenitor/stem cell populations and are capable of regeneration (8,11,38). Recent studies suggest that the adult murine heart also contains such a progenitor cell population and potentially is capable of limited regeneration (3,10,22,28). Analysis of these cardiac progenitor cell populations and the fibroproliferative r...

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This is the first report of HF-related remodeling of outward K+ currents in murine LV. Similar to humans, disease-related remodeling occurs differentially across the murine ventricular wall, leading to loss of the native gradient of repolarization. Together with slowed recovery from inactivation, these alterations likely promote abnormal impulse conduction, a major proarrhythmic mechanism.

Background Several studies have shown that the modulation of fibrotic scar in cardiac diseases has beneficial effects on cardiac arrhythmias. In addition, recent reports suggest a potential role of mineralocorticoid receptor upregulation in atrial fibrillation (AF). The role of spironolactone, a mineralocorticoid receptor blocker and a potent antifibrotic agent, in AF is as yet unexplored. The aim of this study was to determine if spironolactone, a mineralocorticoid receptor blocker with potent antifibrotic properties, has beneficial effects on AF. Hypothesis Spironolactone therapy in patients with atrial fibrillation provides additional clinical benefits in addition to the current conventional pharmacological agents. Methods A comprehensive retrospective analysis was performed on 83 patients with AF, including 23 who were treated with spironolactone for ≥ 3 months. The combined primary outcome of hospitalization for AF or direct current cardioversion (DCCV) was compared between patients treated with spironolactone in addition to the usual care for AF and those receiving conventional medical therapy alone. Results Patients receiving spironolactone had significantly fewer primary outcome events (AF-related hospitalizations or DCCV) (22% vs 53%, P = 0.027). Conclusions Spironolactone therapy is associated with a reduction in the burden of AF, as reflected by a combination of hospitalizations for AF and DCCV. Larger randomized controlled studies should be performed to evaluate the efficacy and safety of spironolactone as an adjunctive therapy for patients with AF.