Abstract 2962: A Elastolytic Cathepsin Induction/Activation System Exists in the Rat and Human Myocardium and is Upregulated in Hypertensive Heart Failure
Background: Cathepsins are cysteine proteases that participate in tissue remodeling. However, the expression of cathepsins during myocardial remodeling has not been examined.
Methods and Results: The expression of cathepsins was examined in the left ventricular (LV) myocardium (LVM) of rats and humans with hypertension-induced LV hypertrophy (H-LVH) or heart failure (H-HF). Reverse transcription and real-time polymerase chain reaction analysis and immunoblot analysis revealed that the abundance of cathepsin S mRNA or protein in the LV myocardium was greater in rats or humans with H-HF than in those with H-LVH or in controls. Expression of cystatin C, an endogenous Cats inhibitor, did not differ between rats or humans with H-HF and controls. Immunohistochemical analysis showed that cathepsin S was localized predominantly to cardiac myocytes and coronary vascular smooth muscle cell (SMC), but also overlapped in part with macrophages. Elastic lamina fragmentations significantly increased in the LVM of H-HF-rats. The amount of elastolytic activity in extracts of the LVM was markedly increased for H-HF rats compared with controls, and this activity was mostly due to cathepsin S. Although the amount of elastin mRNA was increased in the LVM of H-HF rats, the area of interstitial elastin was not. The expression of interleukin-1β was increased in the LVM of H-HF rats, and this cytokine was found to increase the expression and activity of cathepsin S in cultured neonatal cardiomyocytes, SMCs and macrophages.
Conclusions: The presence of cathepsin S at site of cardiovascular matrix remodeling and the ability of cardiomyocytes, SMC, and macrophages to use this enzyme to degrade elastin supports a role for elastolytic cathepsins S in cardiovascular remodeling and identified novel therapheutic targets in preventing or reversing LV remodeling.