Effects of Acute and Chronic Pressure Overload on Myocardial MMP and TIMP Levels

The left ventricle (LV) remodels with age and hypertension (htn), and chronic htn by definition is superimposed on aging. We evaluated the effects of acute and chronic htn on extracellular matrix (ECM) remodeling, by studying the following groups of female Dahl rats: young salt‐resistant (YSR; n=6); young salt‐sensitive (YSS; n=6); middle‐aged salt‐resistant (MAR; n=5); and middle‐aged salt‐sensitive (MAS n=6). The YSS and MAS are acute and chronic htn models, respectively, and YSR and MAR are normotensive age‐matched controls. We measured LV mass and body weight and immunoblotted for a complete panel of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), and ECM proteins. LV mass to body weight ratios increased in MAS, compared to YSS and MAR (p<0.05). In acute htn, active MMP‐8 decreased from 8010±81 units in YSR to 5260±313 units in YSS (p<0.05). TIMP‐1 and collagen were increased, indicating a net fibrotic response. In chronic htn, total collagen decreased to 55% of YSS and 69% of MAR (both p<0.05), and MMP‐3, MMP‐8, and MMP‐14 and fibronectin levels increased (all p <0.05). LV/BW ratio correlated with soluble MMP‐14 (45 kD) in YSS and active MMP‐12 (45 kD) in MAR. The above results suggest a shift from collagen accumulation in the acute htn group to collagen degradation in the chronic htn group. This is the first study to compare ECM changes between acute and chronic htn and to correlate those changes with altered LV/BW ratio. Evaluating ECM changes from acute to chronic htn may suggest mechanisms for how htn progresses from compensatory LV hypertrophy to congestive heart failure.