Cardiosphere-derived cell exosomes delivered IM decrease scarring, halt adverse remodelling and improve LVEF in porcine AMI and CMI. While conceptually attractive as cell-free therapeutic agents for myocardial infarction, exosomes have the disadvantage that IM delivery is necessary.

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Background-The adaptation of cardiac mass to hemodynamic overload requires an adaptation of protein turnover, ie, the balance between protein synthesis and degradation. We tested 2 hypotheses: (1) chronic left ventricular hypertrophy (LVH) activates the proteasome system of protein degradation, especially in the myocardium submitted to the highest wall stress, ie, the subendocardium, and (2) the proteasome system is required for the development of LVH. Methods and Results-Gene and protein expression of proteasome subunits and proteasome activity were measured separately from left ventricular subendocardium and subepicardium, right ventricle, and peripheral tissues in a canine model of severe, chronic (2 years) LVH induced by aortic banding and then were compared with controls. Both gene and protein expressions of proteasome subunits were increased in LVH versus control (PϽ0.05), which was accompanied by a significant (PϽ0.05) increase in proteasome activity. Posttranslational modification of the proteasome was also detected by 2-dimensional gel electrophoresis. These changes were found specifically in left ventricular subendocardium but not in left ventricular subepicardium, right ventricle, or noncardiac tissues from the same animals. In a mouse model of chronic pressure overload, a 50% increase in heart mass and a 2-fold increase in proteasome activity (both PϽ0.05 versus sham) were induced. In that model, the proteasome inhibitor epoxomicin completely prevented LVH while blocking proteasome activation. Conclusions-The increase in proteasome expression and activity found during chronic pressure overload in myocardium submitted to higher stress is also required for the establishment of LVH. Key Words: heart diseases Ⅲ hypertrophy Ⅲ physiology Ⅲ pressure Ⅲ stress Ⅲ proteins L eft ventricular hypertrophy (LVH) is a key compensatory mechanism in response to pressure or volume overload that involves alterations in the regulation of signal transduction pathways, transcription factors, excitation-contraction coupling, contractile proteins, and energy metabolism. One key element of cardiac hypertrophy is an adaptation in protein turnover. Protein turnover refers to protein synthesis and degradation, and both mechanisms are activated by increased cardiac workload. 1,2 Although multiple studies have addressed the activation of protein synthesis during the acute phase of LVH that follows aortic banding, the mechanisms controlling protein degradation in the hypertrophied myocardium, especially over the long term, remain largely unknown. A key mechanism involved in protein degradation is the ubiquitin/proteasome system (UPS), 3 which is known to be an important mechanism mediating muscle atrophy. 4,5 Proteolytic substrates are ligated to multiple ubiquitin (Ub) moieties that are assembled into a chain that binds the proteasome with high affinity. The 26S proteasome contains multiple subunits in the regulatory (19S) particle that can bind multiubiquitinated (multi-Ub) proteins. 6,7 The composition of the proteasome is highl...

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By subtractive hybridization, we found a significant increase in H11 kinase transcript in large mammalian models of both ischemia/reperfusion (stunning) and chronic pressure overload with hypertrophy. Because this gene has not been characterized in the heart, the goal of the present study was to determine the function of H11 kinase in cardiac tissue, both in vitro and in vivo. In isolated neonatal rat cardiac myocytes, adenoviral-mediated overexpression of H11 kinase resulted in a 37% increase in protein/DNA ratio, reflecting hypertrophy. A cardiac-specific transgene driven by the alphaMHC-promoter was generated, which resulted in an average 7-fold increase in H11 kinase protein expression. Transgenic hearts were characterized by a 30% increase of the heart weight/body weight ratio, by the reexpression of a fetal gene program, and by concentric hypertrophy with preserved contractile function at echocardiography. This phenotype was accompanied by a dose-dependent activation of Akt/PKB and p70(S6) kinase, whereas the MAP kinase pathway was unaffected. Thus, H11 kinase represents a novel mediator of cardiac cell growth and hypertrophy.