Drug Targeting of Plasminogen Activator Inhibitor-1 Inhibits Metabolic Dysfunction and Atherosclerosis in a Murine Model of Metabolic Syndrome

Abstract

Objective: Enhanced expression of PAI-1 (plasminogen activator inhibitor-1) has been implicated in atherosclerosis formation in humans with obesity and metabolic syndrome. However, little is known about the effects of pharmacological targeting of PAI-1 on atherogenesis. This study examined the effects of pharmacological PAI-1 inhibition on atherosclerosis formation in a murine model of obesity and metabolic syndrome. Approach and Results: LDL receptor-deficient ( ldlr −/− ) mice were fed a Western diet high in cholesterol, fat, and sucrose to induce obesity, metabolic dysfunction, and atherosclerosis. Western diet triggered significant upregulation of PAI-1 expression compared with normal diet controls. Addition of a pharmacological PAI-1 inhibitor (either PAI-039 or MDI-2268) to Western diet significantly inhibited obesity and atherosclerosis formation for up to 24 weeks without attenuating food consumption. Pharmacological PAI-1 inhibition significantly decreased macrophage accumulation and cell senescence in atherosclerotic plaques. Recombinant PAI-1 stimulated smooth muscle cell senescence, whereas a PAI-1 mutant defective in LRP1 (LDL receptor-related protein 1) binding did not. The prosenescent effect of PAI-1 was blocked by PAI-039 and R2629, a specific anti-LRP1 antibody. PAI-039 significantly decreased visceral adipose tissue inflammation, hyperglycemia, and hepatic triglyceride content without altering plasma lipid profiles. Conclusions: Pharmacological targeting of PAI-1 inhibits atherosclerosis in mice with obesity and metabolic syndrome, while inhibiting macrophage accumulation and cell senescence in atherosclerotic plaques, as well as obesity-associated metabolic dysfunction. PAI-1 induces senescence of smooth muscle cells in an LRP1-dependent manner. These results help to define the role of PAI-1 in atherosclerosis formation and suggest a new plasma-lipid-independent strategy for inhibiting atherogenesis.

A Narrative Review on Plasminogen Activator Inhibitor-1 and Its (Patho)Physiological Role: To Target or Not to Target?

“…Through local inhibition of plasmin generation, PAI-1 can reduce tissue remodeling and potentially stabilize the fibrin matrix of the developing plaque. Furthermore, studies on the effects of pharmacological PAI-1 inhibition on atherogenesis in mice with obesity and metabolic syndrome also suggested a role for PAI-1 in adipose tissue inflammation, macrophage accumulation, and inducing senescence of smooth muscle cells through its interaction with LRP1 [ 49 ]. Whereas several studies demonstrated substantial evidence for PAI-1 as an independent risk factor for CVD including myocardial infarction and stroke [ 50 , 51 , 52 ], coronary heart disease [ 53 ], venous thrombosis [ 54 ], and atherosclerosis [ 45 , 55 ], other studies could not confirm these associations or the significance for the link was lost after adjusting for other risk factors, such as age, sex, and metabolic abnormities [ 52 , 56 , 57 , 58 ].…”

PAI-1, the Plasminogen System, and Skeletal Muscle

“…The investigation of PAI-1 is relevant for clinical application to various disease states [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. PAI-1 levels are elevated in several diseases states and, in rodent models, the ablation/inhibition of PAI-1 tissue repair [ 27 , 28 , 126 , 132 ] whereas deficiency in Plau or other components of the plasminogen system has the opposite effect [ 28 , 35 , 37 , 38 , 40 ].…”

“…Most notable of these inhibitors include tiplaxtinin (PAI-039) and the three generations of TM-related drugs (TM5001, TM5009, TM5275, TM5441, TM5509, and TM5614). These inhibitors have been studied in pathological conditions including cancer, cardiovascular disease, pulmonary fibrosis renal diseases, liver diseases and others [ 17 , 22 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 71 ]. Most if not all of these inhibitors have been shown to bind the active RCL domain on PAI-1 in a reversible manner to ultimately abolish its ability to bind tPA/uPA [ 16 , 69 , 70 ].…”

“…Given that PAI-1 is present within the circulation under normal and pathological conditions, it is unsurprising that this protein is capable of affecting virtually all tissues/organs in the body. For instance, high levels of PAI-1 have been implicated in cancer [ 16 , 17 , 18 , 19 , 20 ], cardiovascular disease [ 21 , 22 , 23 ], diabetic complications [ 23 , 24 ], renal disease [ 25 , 26 ], musculoskeletal disorders [ 27 , 28 , 29 , 30 ], and tissue fibrosis [ 31 , 32 , 33 ]. In skeletal muscle, PAI-1 plays critical roles in response to skeletal muscle injury and in myopathic conditions [ 27 , 28 , 29 , 34 , 35 ], further highlighting the importance of the plasminogen system and ECM remodeling to skeletal muscle.…”

“…Indeed, several studies have identified the importance of plasminogen system function but have yet to fully elucidate a role for PAI-1 in skeletal muscle [ 35 , 36 , 37 , 38 , 39 , 40 ], although recent evidence suggests that skeletal muscle is also a site of PAI-1 synthesis [ 29 , 41 , 42 ]. Control of PAI-1 levels in the circulation is of clinical importance and while studies generally indicate that circulating PAI-1 can be controlled with exercise [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 ] or through the administration of pharmacological PAI-1 inhibitors [ 17 , 22 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. This review will summarize the biology of PAI-1 and the plasminogen system as it relates to overall tissue function and ECM remodeling, highlight the role of PAI-1 in skeletal muscle, and shed light on potential therapeutic strategies to reduce or normalize PAI-1 levels in an attempt to improve muscle and overall health.…”