Inhibiting metalloproteases with PD 166793 in heart failure: impact on cardiac remodeling and beyond.
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.
Kaludercic
Nina
N
Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
Lindsey
Merry L
ML
Tavazzi
Barbara
B
Lazzarino
Giuseppe
G
Paolocci
Nazareno
N
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D015316:Genetic Therapy; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D009842:Oligopeptides / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects*
C370242:(R)-2-(4'-bromo-biphenyl-4-sulfonyl-amino)-3-methyl-butyric acid; D006877:Hydroxamic Acids; D009842:Oligopeptides; D011480:Protease Inhibitors; D045726:Metalloproteases