In high-risk patients, the ideal cardiovascular gene therapy requires a strategy that provides long-term protection of myocardium against episodes of ischemic/reperfusion injury. We report the development of an efficient, long-lasting preemptive gene therapy strategy in a rat model of ischemicreperfusion (I/R) injury of heart. At 6 weeks prior to myocardial injury, the human extracellular superoxide dismutase (Ec-SOD) gene was delivered by direct intramyocardial injections, using a recombinant adeno-associated virus vector. Significant myocardial protection was documented by the decrease in infarct size at 24 h post I/R, improved left ventricular function at 7 weeks postinjury, and enhanced long-term survival in the SOD treated group. This concept of preinjury delivery and 'pre-emptive' gene therapy via the expression of a secreted protein that renders paracrine therapeutic action can be an effective strategy for organ protection against future injury.

Abstract-Matrix metalloproteinase-mediated degradation of type I collagen may play a role in cardiac remodeling after strain or injury. To explore this hypothesis, we used mice homozygous (r/r) for a targeted mutation in Col1a1; these mice synthesize collagen I that resists collagenase cleavage at Gly975-Leu976. . Surprisingly, these differences were not accompanied by differences in collagen accumulation, myocyte cross-sectional areas, wall thickness, or microvessel densities. Furthermore, no differences in LV remodeling assessed by echocardiography, fibrosis, or hemodynamic parameters were found between r/r and WT mice after MI. Thus, a mutation that encodes a collagenase cleavage-resistant collagen I does not affect early LV remodeling after TAC or MI, suggesting that collagen cleavage at this site is not the mechanism by which metalloproteinases mediate LV remodeling. Collagen cleavage could, however, have a role in preservation of cardiac function in late remodeling by mechanisms independent of collagen accumulation. We were not able to detect collagen cleavage fragments, and could not, therefore, rule out the possibility of collagen cleavage at additional sites. Key Words: matrix metalloproteinases Ⅲ collagen Ⅲ left ventricular remodeling Ⅲ myocardial infarction L eft ventricular (LV) remodeling is an important cause of congestive heart failure despite the use of therapeutic agents that inhibit angiotensin II or ␤-adrenergic signaling, highlighting the need for additional understanding of remodeling events. 1 Matrix metalloproteinases (MMPs) comprise a family of enzymes that degrade extracellular matrix and may mediate cardiac remodeling. The expression of certain MMPs increases in nonischemic dilated cardiomyopathy 2 and after myocardial infarction (MI), in the presence or absence of reperfusion. 3,4 Drugs that act as "nonselective" MMP inhibitors prevent ventricular dilation in mice, rats, pigs, and rabbits. [5][6][7][8] In addition, deletion or overexpression of MMPs in mice regulates cardiac remodeling and hypertrophy. 9 -11 The potential roles of MMPs in cardiac remodeling have not yet been fully elucidated. Collagen is the most abundant protein in the body, and collagen I represents about 90% of total collagen. 12 MMP effects on collagen turnover, therefore, may explain effects on remodeling. One hypothesis is that MMPs degrade collagen fibrils and allow cardiomyocytes to "slip" and then establish new matrix attachments. 13 This hypothesis could explain the ventricular dilation that occurs in mice with transgenic overexpression of human MMP-1, 11 a collagenase, the orthologue of which is expressed only at low levels in mice. 14 Alternatively, MMP inhibition could affect the metabolism of a noncollagen molecule that is important in cardiac remodeling. A recent study of selective MMP inhibition supports this hypothesis; administration of an MMP-1 sparing MMP inhibitor prevented LV remodeling after MI in rabbits, a species that utilizes MMP-1 for collagenolysis. 8 To provide insight into these mechani...