The Expression Of Cathepsin S,K And Cystain C During The Left Ventricular Remodeling In Rats With Pressure Overloaded Myocardial Hypertrophy

Objectives:Hypertensive heart disease (HHD) will soon become the most common cause of HF. LV remodeling is an inevitable pathophysiology of hypertension. It involves two primary responses:(1) hypertrophy, dysfunction, and death of cardiac myocytes and (2) increased deposition and alteration of the cardiac extracellular matrix (ECM). In recent years, some study found that cysteine proteases (CPs) also takes part in LV remodeling. Cat S and Cat K are secreted into the extracellular space and manifest elastolytic and collagenolytic activities at a neutral pH. But the activity of Cathepsins is strictly regulated by a family of closely related inhibitors known as cystatins. This investigation tried to observe the expression of cathepsin S, K and cystain C during the left ventricular remodeling in rats with Pressure Overloaded Myocardial Hypertrophy.Methods:Sixty male wistar rats were randomized as follows:4-week sham-operated group (F4), 8-week sham-operated group (F8),4-week aortic-banded group (T4) and 8-week aortic-banded group (T8). Hypertrophy model (H-LVH) and Heart Failure model (H-HF) was established by abdominal aortic constriction. Transthoracic M-mode and two-dimensional echocardiography were performed. The measurements included left ventricular end-diastolic dimension (LVEDD), interventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT). For haemodynamic parameters, left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and systolic blood pressure (SBP) were monitored. The rats were then euthanized, and their hearts harvested, weighed and divided into 2 portions which were fixed in 10% buffered formalin and frozen in liquid nitrogen and then stored at -80℃for later use. The expression of Cat S, K and Cyst C was studied by real-time quantitative PCR and by immuneohistochemistry. The myocardial fibrosis was analyzed with picrosirius red staining.Results:1. Echocardiography and Haemodynamic MeasurementsCompared with rats in F4 group, left ventricular mass index (LVMI), SBP, IVST, LVPWT from T4 group showed increased (P<0.05). Compared with rats in F8 group, LVMI, SBP, IVST, LVPWT from T8 group showed significantly increased (P<0.05), and some signs of heart failure were observed such as dyspnoea, abdominal distension and lethargic activity.2. Fibrosis of LV myocardiumCompared with rats in F4 group, the collagen volume fraction (CVF) and perivascular collagen area (PVCA) from T4 group showed increased (P<0.01). While compared with rats in F8 group, CVF and PVCA from T8 group showed significantly increased (P<0.01).3. Expression of Cat S, K and Cyst C by immuneohistochemistryCompared with rats in F4 group, the expression of Cat S, K and Cyst C from T4 group showed increased (P<0.05). Compared with rats in F8 group, the expression of Cat S, K from T8 group showed significantly increased (P<0.01), but the expression of Cyst C had no significant difference.4. Expression of Cat S, K and Cyst C mRNA in ratsCompared with rats in F4 group, the expression of Cat S, K and Cyst C from T4 group showed significantly increased (P<0.01). In T8 group the expression of CatS, K mRNA was increased dramatically compared with F8 group (P<0.01). But the expression of Cyst C mRNA fell to normal levels.Conclusions:1. Cathepsin S, K and cystain C play an important role in the left ventricular remodeling with pressure overloaded myocardial hypertrophy.2. The imbalance between Cat S, K and Cyst C in the left ventricular (LV) myocardium results in quantity and quality changes in the LV ECM components and their balances and translation from left ventricular hypertrophy to heart failure.