Plasminogen Deficiency Significantly Reduces Vascular Wall Disease in a Murine Model of Type IIa Hypercholesterolemia

Abstract

The fibrinolytic system has been implicated in the genesis and progression of atherosclerosis. It has been reported that a plasminogen (Pg) deficiency (Plg−/−) exacerbates the progression of atherosclerosis in Apoe−/− mice. However, the manner in which Plg functions in a low-density lipoprotein-cholesterol (LDL-C)-driven model has not been evaluated. To characterize the effect of Pg in an LDL-C-driven model, mice with a triple deficiency of the LDL-receptor (LDLr), along with the active component (apobec1) of the apolipoprotein B editosome complex, and Pg (L−/−/A−/−/Plg−/−), were generated. Atherosclerotic plaque formation was severely retarded in the absence of Pg. In vitro studies demonstrated that LDL uptake by macrophages was enhanced by plasmin (Pm), whereas circulating levels of LDL were enhanced, relative to L−/−/A−/− mice, and VLDL synthesis was suppressed. These results indicated that clearance of lipoproteins in the absence of LDLr may be regulated by Pg/Pm. Conclusions: The results from this study indicate that Pg exacerbates atherosclerosis in an LDL-C model of atherosclerosis and also plays a role in lipoprotein modification and clearance. Therefore, controlling the Pg system on macrophages to prevent foam cell formation would be a novel therapeutic approach.

Inhibition of plasminogen suppresses fibrosis and macrophage foaming in a nonalcoholic steatohepatitis mouse model

“…Liver macrophage foaming is one of the key factors in understanding the pathophysiology of NASH, and we were able to assess foaming using L −/− / A −/− mice. In L −/− /A −/− /Plg −/− mice, macrophage foaming in NASH was suppressed, which is consistent with atherosclerosis [14–16] (Figure 3). The above was also observed upon administration of TXA, which inhibits lysine‐mediated binding of Plg (Figure 3).…”

“…Plasminogen-deficient mice (Plg À/À ) and L À/À /A À/À mice, previously described [20,[22][23][24][25], were backcrossed with the C57Bl/6J strain (Jackson Laboratory, Bar Harbor, ME, USA) for at least seven generations before cross-breeding. Triple heterozygous (L +/À /A +/À / Plg +/À ) mice were crossed with L À/À /A À/À mice to produce L À/À /A À/À /Plg +/À mice [16]. The control mice were injected with saline at 1 to 3 days of age and only male mice were fed the standard diet (5L37; PMI Nutrition International, St. Louis, MO, USA) from 28 days of age.…”

“…In clinical practice, plasma Plg levels are elevated in patients with atherosclerosis [11–13]. Plg also promotes macrophage foaming in vitro and aggravates atherosclerosis, a major disease caused by macrophage foaming, in an animal model [14–16]. These results suggest that elevated Plg is not a consequence, but instead a cause, of macrophage foaming.…”

Role of thyroid hormone in an experimental model of atherosclerosis: the potential mediating role of immune response and autophagy

“…We have recently revealed that the L -/-/A -/mice develop atherosclerotic plaques with several key features of LDL-driven atherosclerosis reported in the patients with type IIa dyslipidemia [69]. We have also provided evidence that this mouse model is useful for studying the pathophysiology of several diseases, including fibrinogen deficiency, plasminogen deficiency, and aortic aneurysms, in relation to LDLcholesterol-driven atherosclerosis [68,70,72].…”

“…The frequencies of each type in Japanese male population were reported as 0.1%, 32.2%, 20.9%, 0.3%, 44.6%, and 1.9%, respectively; while those in Japanese female population were reported as 0.3%, 53.3%, 22.8%, 0.7%, 21.5%, and 1.4%, respectively [67]. Although mice deficient in apoE or Ldlr have been extensively used, mice that are fed a normal chow diet do not mimic type IIa dyslipidemia, which is one of the most common types in human dyslipidemia [68][69][70].…”