![]() ![]() 3, 11 In this study, we report 2 cases of cardiac fibrosis because of complete PAI-1 deficiency in humans, validating our observations in murine models of cardiac fibrosis and broadening the significance of PAI-1 in mammalian cardiovascular disease. 9, 10 Paradoxically, 2 previous studies established that genetic deficiency of PAI-1 promotes spontaneous cardiac-selective fibrosis during aging in mice. 8 In organs such as the liver, skin, lung, and kidney, PAI-1 exerts a profibrotic effect by its inhibition of the plasmin-MMP system, which is responsible for the clearance of collagen and fibrin. Plasminogen activator inhibitor type I (PAI-1) is a member of the serine protease inhibitor superfamily, inhibits the plasminogen system, negatively regulates the activation of matrix metalloproteinases (MMPs), and is important for tissue homeostasis. ![]() Currently, organ transplantation represents the only effective cure for end-stage fibrotic disease. 7 Various molecular mechanisms for cardiac fibrosis have been proposed, yet limited availability of targeted pharmacotherapy highlights the need for further investigation. 6 The presence and extent of clinically detectable cardiac fibrosis is a major independent predictive factor of adverse cardiac outcomes in multiple clinical trials. 5 Heart failure currently represents the leading healthcare expenditure in the United States, and the estimated total lifetime risk for cardiovascular disease is estimated to be 35.3%. Scar disrupts normal tissue architecture and adversely affects biochemical and mechanical properties of the myocardium, leading to defects in filling and contractility. 1– 4 Excessive cardiac remodeling after both acute and chronic injury leads excessive deposition of fibrotic extracellular matrix (ECM), including collagen. Transcriptome analysis of ventricular RNA after Angiotensin II treatment confirmed that PAI-1 deficiency significantly enhanced multiple TGF-β signaling elements and transcriptional targets, including genes for extracellular matrix components, mediators of extracellular matrix remodeling, matricellular proteins, and cardiac integrins compared with wild-type mice.Ĭardiac fibrosis is a common pathologic feature of a broad spectrum of cardiovascular diseases, including pulmonary arterial hypertension, hypertensive heart disease, dilated cardiomyopathy, and myocardial infarction. ![]() Furthermore, ventricular myocytes were found to be an important source of cardiac transforming growth factor-β (TGF-β) and PAI-1 regulated TGF-β synthesis by cardiomyocytes in vitro as well as in vivo during cardiac injury. ![]() Although Angiotensin II-induced hypertension was blunted in PAI-1 −/− mice, cardiac hypertrophy was accelerated. Treatment of young PAI-1 −/− mice with Angiotensin II induced extensive hypertrophy and fibrotic cardiomyopathy, with increased cardiac apoptosis and both reactive and replacement fibrosis. In addition to its suppressive role during spontaneous cardiac fibrosis in multiple species, we hypothesized that PAI-1 also regulates fibrosis during cardiac injury. Cardiac fibrosis was detected in 2 otherwise healthy humans with complete PAI-1 deficiency because of a homozygous frameshift mutation in SERPINE-1. ![]()
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