Infusion of angiotensin II increases fibrinolysis in healthy individuals but not in patients with familial combined hyperlipidemia

Abstract

Impaired fibrinolysis is related to insulin resistance, also a characteristic feature of familial combined hyperlipidemia (FCHL). The renin-angiotensin (Ang) system is upregulated with insulin resistance, and there is crosstalk between Ang II and insulin-signalling pathways. We studied the fibrinolytic effects of a 3-h systemic Ang II infusion in 16 patients with FCHL and 16 controls, and placebo infusion in eight individuals. Baseline plasminogen activator inhibitor-1 (PAI-1) activity, plasmin-antiplasmin complex, insulin resistance and C-reactive protein were higher in patients with FCHL than in controls. PAI-1 activity decreased during Ang II, similar in patients with FCHL and controls, and by placebo. Plasmin-antiplasmin complex was unaffected by Ang II in FCHL but increased in controls. Patients with FCHL show signs of insulin resistance, low-grade inflammation and impaired fibrinolysis. Ang II enhances fibrinolysis in controls but not in patients with FCHL, suggesting that patients with FCHL are not capable of increasing tissue plasminogen activator activity in response to Ang II. Ang II has no short-term effects on PAI-1 activity.

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“…In conflict, Ang II did not involve any changes in PAI-1 antigen or activity in healthy subjects in other studies ( Larsson et al, 1999 ; Lottermoser et al, 2004 ). We observed no effects on PAI-1 activity during Ang II infusion during 3 h in control subjects, patients with familial combined hyperlipidemia, or with familial hypercholesterolemia ( Ekholm et al, 2015 ; Ekholm et al, 2016 ), ( Figure 8 ). Thus, Ang II may induce PAI-1 release in the long-term setting, possibly by a shift of the endothelial cells to a proinflammatory phenotype, but we could not find any short-term impact of Ang II on the concentrations of PAI-1.…”

“…Thus, Ang II may induce PAI-1 release in the long-term setting, possibly by a shift of the endothelial cells to a proinflammatory phenotype, but we could not find any short-term impact of Ang II on the concentrations of PAI-1. In addition, we observed that Ang II infusion also seems to induce a progressive increase in tPA activity in healthy volunteers ( Ekholm et al, 2016 ). The response to Ang II stimulation in patients with chronic diseases such as cardiovascular disease or diabetes mellitus, which implies endothelial dysfunction, is not known.…”

“…This is in contrast to a previously reported increase in TAT complex and a tendency to increased F1+2 during short-time Ang II infusion in healthy males ( Larsson et al, 2000 ). However, F1+2 exhibits a diurnal decrease during morning hours ( Kapiotis et al, 1997 ; Ekholm et al, 2016 ) and these possible effects of diurnal variations of these markers were initially not taken into account by us ( Ekholm et al, 2009 ; Ekholm et al, 2015 ). The absence of the expected diurnal decreases in F1+2 concentrations during morning hours, during stimulation by Ang II, may be considered as a relative increase in thrombin generation, similar to findings in healthy subjects ( Larsson et al, 2000 ) and in familial combined hyperlipidemia patients ( Ekholm et al, 2009 ).…”

“…The effect of physiological saline infusion in placebo experiments, green line and unfilled triangles ( n = 8), is also shown. Data from ( Ekholm et al, 2009 ; Ekholm et al, 2015 ; Ekholm et al, 2016 ).…”