Fibrinolytic System in the Regulation of Cardiac Fibrosis
Heart disease is the number one cause of deaths worldwide, claiming more than 1 million lives per year. Most patients who suffer from heart disease have scarring of cardiac tissue (cardiac fibrosis), the result of pathological wound healing processes following cardiac tissue injury. The physiological outcome of this dysregulated wound healing process is associated with increased deposition of extracellular matrix in the myocardium and stiffening of the cardiac tissue with resultant diminishment of heart function. However, the mechanisms associated with the development of cardiac fibrosis remain largely unknown.
Several reports demonstrated the involvement of hemostasis proteins in cardiac fibrosis. Studies in our laboratory have shown that mice deficient for plasminogen activator inhibitor-1 (PAI-1-/-) spontaneously develop cardiac fibrosis with aging which is preceded by bleeding and inflammation and ultimately dysregulated tissue remodeling. Our results suggest that PAI-1 is cardioprotective, and functions in maintaining normal microvasculature integrity.
The focus of the current study is to further investigate the contribution of components of the fibrinolytic system in early and late events of cardiac fibrosis in both nonhypertensive, and angiotensin II/aldosterone-induced hypertensive model. For these studies, we will utilize molecular, cellular, and biochemical approaches, as well as mouse models either deficient in or expressing mutant forms of fibrinolytic system proteins.
Macroscopic views of cardiac fibrosis. Top panel: hearts from WT mice at indicated time points. Bottom panel: hearts from PAI-1-/- mice at indicated time points.
Gupta KK, Donahue DL, Sandoval-Cooper MJ, Castellino FJ, Ploplis VA. Plasminogen Activator Inhibitor-1 Protects Mice Against Cardiac Fibrosis by Inhibiting Urokinase-type Plasminogen Activator-mediated Plasminogen Activation. Sci Rep. 2017 Mar 23;7(1):365. doi: 10.1038/s41598-017-00418-y. PMID: 28336948
Xu Z, Castellino FJ, Ploplis VA. Plasminogen activator inhibitor-1 (PAI-1) is cardioprotective in mice by maintaining microvascular integrity and cardiac architecture. Blood. 2010 Mar 11;115(10):2038-2047. doi: 10.1182/blood-2009-09-244962. Epub2009 Dec 15. PMID:20009036
Xu H, Noria F, Sandoval-Cooper MJ, Menchen H, Donahue DL, Ploplis VA, Castellino FJ. Severe deficiency of coagulation Factor VII results in spontaneous cardiac fibrosis in mice. J Pathol. 2009 Feb;217(3):362-371. doi: 10.1002/path.2454. PMID:18973189 217:362-371.