Abstract
Previously published, off-target effects of statins on skeletal smooth muscle function have linked structural characteristics within this drug class to myopathic effects. However, the effect of these drugs on lymphatic vascular smooth muscle cell function, and by proxy dietary cholesterol uptake, by the intestinal lymphatic network has not been investigated. Several of the most widely prescribed statins (Atorvastatin, Pravastatin, Lovastatin, and Simvastatin) were tested for their in-situ effects on smooth muscle contractility in rat mesenteric collecting lymphatic vessels. Lovastatin and Simvastatin had a concentration-dependent effect of initially increasing vessel contraction frequency before flatlining the vessel, a phenomenon which was found to be a lactone-ring dependent phenomenon and could be ameliorated through use of Lovastatin- or Simvastatin-hydroxyacid (HA). Simvastatin treatment further resulted in mitochondrial depolymerization within primary-isolated rat lymphatic smooth muscle cells (LMCs) while Lovastatin was found to be acting in a mitochondrial-independent manner, increasing the function of RhoKinase. Lovastatin’s effect on RhoKinase was investigated through pharmacological testing and in vitro analysis of increased MLC and MYPT1 phosphorylation within primary isolated LMCs. Finally, acute in vivo treatment of rats with Lovastatin, but not Lovastatin-HA, resulted in a significantly decreased dietary lipid absorption in vivo through induced disfunction of mesenteric lymph uptake and trafficking.
Highlights
Lymphatic vessels transport lymph, consisting of interstitial fluid, immune cells, antigens, and other macromolecules, to the lymph nodes for antigen screening and into blood circulation [1]
We demonstrate that all these effects are specific to the use of the closed lactone-ring form of Lovastatin as, Lovastatin-hydroxyacid did not lead to significant alteration in cholesterol bio-distribution compared to sham controls, suggesting the conserved inhibitory effect of the lactone ring in vivo (Figure 6A–C)
Using isolated rat lymphatic smooth muscle cells, paired with mitochondrial staining and imaging, we demonstrated that the pro-drug form of Simvastatin, but not Lovastatin, had a significant impact on mitochondrial dynamics
Summary
Lymphatic vessels transport lymph, consisting of interstitial fluid, immune cells, antigens, and other macromolecules, to the lymph nodes for antigen screening and into blood circulation [1]. Lymphatic pumping is tightly regulated by intrinsic and extrinsic factors, many of them derived from the endothelial or smooth muscle cells [3,4] These factors include chemical mediators such as nitric oxide (NO) or prostaglandins [5,6,7,8]. While lymphatic disfunction is frequently observed at sites of inflammation and infection, it is commonly overlooked due to an incomplete understanding of its role in the disease’s pathology. These changes result in a variety of outcomes, including decreased fluid drainage (lymphedema) and reduced nutrient absorption (malnutrition)
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