IngentaConnect Inhibiting Metalloproteases with PD 166793 in Heart Failure: Impa...

Authors: Kaludercic, Nina¹; Lindsey, Merry L.²; Tavazzi, Barbara³; Lazzarino, Giuseppe⁴; Paolocci, Nazareno

Source: Cardiovascular Drug Reviews, Volume 26, Number 1, Spring 2008 , pp. 24-37(14)

Abstract:

Metalloproteinases (MMPs, also called matrixins) are extracellular proteolytic enzymes involved in the degradation of both matrix and nonmatrix proteins. Currently, 25 MMPs have been identified in humans, and the overexpression of one or more MMPs has been implicated in several pathologies, spanning from cancer to rheumathoid arthritis to cardiovascular disease. While research over the past 20 years has focused on understanding MMP biology and selectively inhibiting MMP activity, key issues that remain to be addressed include MMP roles in the context of normal versus pathological conditions and whether globally inhibiting MMPs improves or deteriorates overall organ function. In terms of cardiovascular disease, increased MMP expression has been demonstrated in the setting of myocardial ischemia, reperfusion injury, and during the progression to congestive heart failure. MMPs are also major contributors to the progression of atherosclerotic lesions. In this review, we focus on cardiovascular effects produced by PD 166793, a wide-broad spectrum MMP inhibitor, originally developed by Parke-Davis (now Pfizer). We will briefly review its structure, mechanism of action, and inhibitory capacity. Finally, we will illustrate the cardiac contexts, both in vivo and in vitro, in which PD166793 administration has proven beneficial.

Keywords: AMP deaminase; Cardiac energetics; Heart failure; Metalloproteinases; Myocardial fibrosis; PD166793; Ventricular remodeling

Document Type: Research article

DOI: 10.1111/j.1527-3466.2007.00034.x

Affiliations: 1: Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD, USA 2: University of Texas Health Science Center, San Antonio, Texas, USA 3: Institute of Biochemistry, Catholic University of Rome, Italy 4: Department of Chemical Sciences, University of Catania, Catania, Italy

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Inhibiting Metalloproteases with PD 166793 in Heart Failure: Impact on Cardiac Remodeling and Beyond