Heart failure is a leading cause of morbidity and mortality in industrialized countries. Although infection with microorganisms is not involved in the development of heart failure in most cases, inflammation has been implicated in the pathogenesis of heart failure1. However, the mechanisms responsible for initiating and integrating inflammatory responses within the heart remain poorly defined. Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA2,3,4. Mitochondria damaged by external hemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes5. Here, we show that mitochondrial DNA that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated inflammatory responses in cardiomyocytes and is capable of inducing myocarditis, and dilated cardiomyopathy. Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions, but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload. Early in the pathogenesis, DNase II-deficient hearts exhibited infiltration of inflammatory cells and increased mRNA expression of inflammatory cytokines, with accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium. Administration of the inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA6, or ablation of Tlr9 attenuated the development of cardiomyopathy in DNase II-deficient mice. Furthermore, Tlr9-ablation improved pressure overload-induced cardiac dysfunction and inflammation even in mice with wild-type Dnase2a alleles. These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.

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Abstract-Cardiomyocyte death plays an important role in the pathogenesis of heart failure. The nuclear factor (NF)-B signaling pathway regulates cell death, however, the effect of NF-B pathway on cell death can vary in different cells or stimuli. The purpose of the present study was to clarify the in vivo role of the NF-B pathway in response to pressure overload. First, we subjected C57Bl6/J mice to pressure overload by means of transverse aortic constriction (TAC) and examined the activity of the NF-B pathway in response to pressure overload. IB kinase (IKK) and NF-B were activated after TAC. Then, we investigated the role of the activation using cardiac-specific IKK␤-deficient mice (CKO). CKO displayed normal global cardiac structure and function compared with control littermates. We subjected CKO and control mice to pressure overload. One week after TAC, CKO showed cardiac dilation, dysfunction, and lung congestion, which are characteristics of heart failure. The number of apoptotic cells in the hearts of CKO mice increased significantly after TAC. The levels of manganese superoxide dismutase mRNA and protein expression in CKO after TAC were significantly attenuated compared with control mice. The levels of oxidative stress and c-Jun N-terminal kinase (JNK) activation in CKO after TAC were significantly greater than those in control mice. Isoproterenol-induced cell death of isolated adult CKO cardiomyocytes was inhibited by treatment with either a manganese superoxide dismutase mimetic or a JNK inhibitor. Thus, the IKK␤/NF-B signaling pathway plays a protective role in cardiomyocytes because of the attenuation of oxidative stress and JNK activation in a setting of acute pressure overload. Key Words: heart failure Ⅲ apoptosis Ⅲ NF-B C ardiac remodeling is generally accepted as a determinant of the clinical course of heart failure. Cardiomyocyte apoptotic death plays an important role in the progression of cardiac remodeling. [1][2][3][4] The loss of cardiomyocytes caused by apoptosis is predicted to reduce contractility and promote slippage of muscle bundles, wall thinning, and dilatation, which are commonly observed during heart failure. Neurohumoral factors and cytokines that are induced by mechanical stress on cardiomyocytes activate various intracellular signaling pathways, which regulate apoptotic cell death.The nuclear factor (NF)-B transcription factors (p50, p52, RelA, c-Rel, and RelB) play important roles in many physiological and pathological conditions. These transcriptional factors are kept inactive in the cytoplasm by binding of inhibitory proteins, the IB (inhibitor of NF-B) family. On stimulation, IBs are phosphorylated at serine residues, leading to their ubiquitination and degradation by the 26S proteasome. The freed NF-B components dimerize and translocate to nucleus, where they bind to specific sequences in either the promoter or enhancer regions of target genes. 5 Activation process is dependent on phosphorylation of IB proteins, which is mediated by the IKK complex. The IKK complex is comp...

The effect of cross-linking on intercellular polymer diffusion in poly(butyl methacrylate-co-butyl acrylate-co-ethylene glycol dimethacrylate) latex films containing 0.1−4 mol % ethylene glycol dimethacrylate (EGDMA) as a cross-linking agent was monitored by fluorescent energy-transfer measurements and by atomic force microscopy. The presence of cross-links in the latex particles limits the extent of polymer interdiffusion. The extent of mixing caused by this polymer diffusion decreased with increasing levels of cross-linking. Even, however, in films containing 4 mol % EGDMA, significant polymer diffusion occurred. To explain polymer diffusion in latex films with 100% gel content, we imagine that the intercellular mixing is caused by diffusion of dangling polymer chains anchored in the cross-linked network. These cross-linked latex particles form tough elastomeric films (with T g estimated to be 10 °C), characterized by high tensile strength and substantial elongation to break (>100% elongation). The films have poor resistance to organic solvents.

Background: Rheb (Ras homologue enriched in brain) regulates mammalian target of rapamycin complex 1 (mTORC1). Results: mTORC1 activity and cardiac hypertrophy are attenuated in Rheb-deficient hearts after the early postnatal period. Conclusion: Rheb-dependent mTORC1 activation becomes essential for cardiomyocyte hypertrophic growth after the early postnatal period. Significance: The findings provide insight into the regulatory mechanism of mTORC1 in postnatal heart development.

Polystyrene particles incorporating poly(methylphenylsilane) (PMPS) were synthesized by miniemulsion polymerization. UV irradiation of the emulsion under air in the presence of metal salts such as HAuCl4.4H2O, AgNO3, and Na2PdCl4 led to the formation of metal nanoparticles on the surface of polymer particles; thus, metal nanoparticle/polymer hybrid particles were obtained. The structures of the hybrid particles were confirmed by the surface plasmon resonance band and transmission electron microscopy images. The formation of metal nanoparticles depended on the functional groups and charge on the surface of the polymer particle. The metal nanoparticles were formed due to the reduction of metal ions, accompanied by the oxidation of PMPS. The interaction between the surface of the polymer particle and the metal ions plays an important role in the formation of the metal nanoparticle.

Calpains make up a family of Ca 2؉ -dependent intracellular cysteine proteases that include ubiquitously expressed -and m-calpains. Both are heterodimers consisting of a distinct large catalytic subunit (calpain 1 for -calpain and calpain 2 for m-calpain) and a common regulatory subunit (calpain 4). The physiological roles of calpain remain unclear in the organs, including the heart, but it has been suggested that calpain is activated by Ca 2؉ overload in diseased hearts, resulting in cardiac dysfunction. In this study, cardiac-specific calpain 4-deficient mice were generated to elucidate the role of calpain in the heart in response to hemodynamic stress. Cardiac-specific deletion of calpain 4 resulted in decreased protein levels of calpains 1 and 2 and showed no cardiac phenotypes under base-line conditions but caused left ventricle dilatation, contractile dysfunction, and heart failure with interstitial fibrosis 1 week after pressure overload. Pressure-overloaded calpain 4-deficient hearts took up a membrane-impermeant dye, Evans blue, indicating plasma membrane disruption. Membrane repair assays using a two-photon laser-scanning microscope revealed that calpain 4-deficient cardiomyocytes failed to reseal a plasma membrane that had been disrupted by laser irradiation. Thus, the data indicate that calpain protects the heart from hemodynamic stresses, such as pressure overload.

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