alpha-chymotrypsin and Heart-Failure

Recent reports demonstrate that multiple forms of cardiovascular stress, including pressure overload, chronic ischemia, and infarction-reperfusion injury, provoke an increase in autophagic activity in cardiomyocytes. However, nothing is known regarding molecular events that stimulate autophagic activity in stressed myocardium. Because autophagy is a highly conserved process through which damaged proteins and organelles can be degraded, we hypothesized that stress-induced protein aggregation is a proximal trigger of cardiomyocyte autophagy.. Here, we report that pressure overload promotes accumulation of ubiquitinated protein aggregates in the left ventricle, development of aggresome-like structures, and a corresponding induction of autophagy. To test for causal links, we induced protein accumulation in cultured cardiomyocytes by inhibiting proteasome activity, finding that aggregation of polyubiquitinated proteins was sufficient to induce cardiomyocyte autophagy. Furthermore, attenuation of autophagic activity dramatically enhanced both aggresome size and abundance, consistent with a role for autophagic activity in protein aggregate clearance.. We conclude that protein aggregation is a proximal trigger of cardiomyocyte autophagy and that autophagic activity functions to attenuate aggregate/aggresome formation in heart. Findings reported here are the first to demonstrate that protein aggregation occurs in response to hemodynamic stress, situating pressure-overload heart disease in the category of proteinopathies.

Topics: Animals; Animals, Newborn; Autophagy; Cells, Cultured; Chymotrypsin; Genes, Reporter; Heart Diseases; Heart Failure; Heart Ventricles; Male; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Pressure; Proteins; Rats; Rats, Sprague-Dawley; Transfection; Ubiquitin; Ventricular Function

Topics: Ascitic Fluid; Chymotrypsin; Heart Failure; Humans; Liver Cirrhosis; Neoplasms; Pancreatitis; Pleural Effusion; Protease Inhibitors; Trypsin Inhibitors

Topics: Aerosols; Air Pollution; Aminophylline; Anti-Bacterial Agents; Body Weight; Bronchitis; Bronchitis, Chronic; Bronchodilator Agents; Central Nervous System Stimulants; Chymotrypsin; Cysteine; Emphysema; Heart Failure; Isoproterenol; Muscle Relaxants, Central; Oxygen Inhalation Therapy; Parasympatholytics; Pulmonary Emphysema; Respiratory Insufficiency; Smoking; Sputum; Sulfonamides; Sympathomimetics; Therapeutics

Topics: Asthma; Bronchitis; Chymotrypsin; Drug Therapy; Emphysema; Heart Failure; Humans; Peptide Hydrolases; Pulmonary Emphysema; Pulmonary Fibrosis; Sputum; Trypsin; Tuberculosis; Tuberculosis, Pulmonary; Viscosity