Drago Robert Sliskovic

Matrix Metalloproteinase Inhibition Attenuates Left Ventricular Remodeling and Dysfunction in a Rat Model of Progressive Heart Failure

BackgroundMatrix metalloproteinase (MMP) activation contributes to tissue remodeling in several disease states, and increased MMP activity has been observed in left ventricular (LV) failure. The present study tested the hypothesis that MMP inhibition would influence LV remodeling and function in developing LV failure. Methods and ResultsLV size and function were measured in 5 groups of rats: (1) obese male spontaneously hypertensive heart failure rats (SHHF) at 9 months (n=10), (2) SHHF at 13 months (n=12), (3) SHHF rats treated with an MMP inhibitor during months 9 to 13 (PD166793 5 mg · kg−1 · d−1 PO; n=14), (4) normotensive Wistar-Furth rats (WF) at 9 months (n=12), and (5) WF at 13 months (n=12). Plasma concentrations of the MMP inhibitor (116±11 &mgr;mol/L) reduced in vitro LV myocardial MMP-2 activity by ≈100%. LV function and geometry were similar in WF rats at 9 and 13 months. LV peak +dP/dt was unchanged at 9 months in SHHF but by 13 months was reduced in the SHHF group compared with WF (3578±477 versus 5983±109 mm Hg/s, P ≤0.05). LV volume measured at an equivalent ex vivo pressure (10 mm Hg) was increased in SHHF at 9 months compared with WF (443±12 versus 563±33 mL, P ≤0.05) and increased further by 13 months (899±64 mL, P ≤0.05). LV myocardial MMP-2 activity was increased by ≈2-fold in SHHF at 9 and 13 months. With MMP inhibition, LV peak +dP/dt was similar to WF values and LV volume was reduced compared with untreated SHHF values (678±28 mL, P ≤0.05). ConclusionsMMP activity contributes to LV dilation and progression to LV dysfunction in a rodent HF model, and direct MMP inhibition can attenuate this process.

ACAT inhibitors: the search for a novel and effective treatment of hypercholesterolemia and atherosclerosis.

Publisher Summary This chapter explores that many different clofibrate-type compounds soon appeared with some desirable features, and a unifying molecular mechanism now exists for these drugs, none of them are particularly efficacious with regard to cholesterol reduction, especially low-density lipoprotein-cholesterol (LDL-cholesterol). They have been most useful for triglyceride reduction and to some extent, elevation of high-density lipoprotein-cholesterol (HDL-cholesterol). Thus, other drugs were sought, resulting in the emergence of compounds that inhibit specific steps in the cholesterol biosynthetic pathway. This emphasis led to the discovery of the HMG-CoA reductase inhibitors, now the dominant class of drugs widely used for the treatment of hypercholesterolemia. The chapter describes the biology and pharmacology of another class of potential cholesterol-lowering agents—namely, inhibitors of the intracellular enzyme, acyl-CoA:cholesterol O-acyltransferase (ACAT). It discusses that ACAT catalyzes the conversion of unesterified (free) cholesterol to cholesteryl esters in virtually every tissue, especially liver, intestine, and the endocrine organs, and, thereby plays a major role in intracellular cholesterol homeostasis. The chapter focuses on lipoprotein-producing tissues, with an additional emphasis on specific cells within developing atherosclerotic lesions. The biology of ACAT is briefly discussed for these tissues, and comprehensive evaluation is done for ACAT inhibitors that have emerged.