Figure 11

Potential interactions among various mediator pathways in the regulation of MMP expression and in the subsequent development of PH. Schematic depiction of molecular mechanisms responsible for MMP transcriptional regulation. Growth factors such as tyrosine kinases (TK), endothelin system (ET) and serine elastases (S.Elastases) positively modulate several MMP genes transcription. MMPs that were produced then cleave extracellular matrix (ECM) and thereby promotes SMC migration and proliferation. Augmentation of these processes ultimately leads to pulmonary vascular remodeling and PH. In contrast, mediators that influence cAMP pathway (Prostacyclin analogues (PGI₂) and combined PDE 3/4 inhibitors (tolafentrine) and to a less extent nitric oxide (NO) represses MMP gene activation that were positively modulated by various growth factors during development of PH. These effects eventually lead to regression of matrix degradation, SMC migration and proliferation and reverse-remodeling of pulmonary arteries. GF, growth factor; TK, tyrosine kinase; MEK, MAP/ERK kinase; ERK, Extracellular signal-regulated kinase; IP, prostaglandin I2 (prostacyclin) receptor; AC, adenylyl cyclase; PDE3, phosphodiesterase isoenzyme 3; PDE4, phosphodiesterase isoenzyme 4; iPKA, inhibitory protein kinase A; aPKA, activated protein kinase A; S.Elastases, serine elastases; NO, nitric oxide; ATF3, activating transcription factor 3; ET, endothelin; ETR, endothelin receptor; AP1, activator protein 1; CREB, CRE-binding protein; NFkβ, Sp1, Sp1, transcription factor; NF-kB, nuclear factor-kappaB (p65); MMP, matrix metallo proteases; ECM, extracellular matrix.