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...

We examined the role of p38α MAPK in mediating cardiomyopathy in mice overexpressing β 1 -adrenergic receptor (β 1 -AR) or β 2 -AR by mating them with dominant-negative p38α (DNp38α) MAPK mice. Both β 1 -AR and β 2 -AR Tg mice had enhanced LV ejection fraction (LVEF) as young adults and developed similar cardiomyopathy at 11-15 months, characterized by reduced LVEF, myocyte hypertrophy, fibrosis, and apoptosis. We inhibited p38α MAPK by mating β 1 -AR Tg and β 2 -AR Tg mice with DNp38α MAPK mice, which rescued the depressed LVEF and reduced apoptosis and fibrosis in bigenic β 2 -AR × DNp38α MAPK mice, but not bigenic β 1 -AR × DNp38α MAPK mice, and failed to reduce myocyte hypertrophy in either group. G sα was increased in both β 1 -AR Tg and β 2 -AR Tg mice and was still present in bigenic β 1 -AR × DNp38α MAPK mice, but not bigenic β 2 -AR × DNp38α MAPK mice. This suggests that p38α MAPK is one critical downstream signal for the development of cardiomyopathy following chronic β 2 -AR stimulation, but other kinases may be more important in ameliorating the adverse effects of chronic β 1 -AR stimulation.

Oesophageal functions were measured in 18 patients with angina, 13 healthy volunteers and 29 age-matched patients with reflux disease. Acid clearance was as abnormal in angina patients (88 +/- 46 swallows) as in those with reflux disease (97 +/- 45). The pressure in the lower oesophageal sphincter was low in patients with angina (13 +/- 8 mm Hg). The incidence of hiatal hernia, subjective symptoms during acidification of the oesophagus and results of the reflux provocation test were similar in patients with angina pectoris and healthy controls.

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