Prelamin A Does Not Promote Atherosclerosis or Vascular Smooth Muscle Loss

Abstract

BACKGROUNDHutchinson-Gilford progeria syndrome (HGPS) is an accelerated aging disorder characterized by numerous symptoms, including early-onset atherosclerosis, with most patients suffering fatal myocardial infarctions or strokes by the second decade of life. HGPS is caused by mutations in LMNA that lead to expression of an internally truncated, farnesylated prelamin A variant called progerin, which induces loss of vascular smooth muscle cells (VSMCs). Some studies have also reported that accumulation of full-length farnesylated prelamin A, which is normally completely processed to mature non-farnesylated lamin A, can also drive vascular pathology during physiological aging. METHODSTo assess the effects of prelamin A expression on atherosclerosis and aortic VSMCs, we used LmnaL648R/L648R mice that express a prelamin A variant with a lysine to arginine point mutation that prevents its processing to mature lamin A. To determine if prelamin A expression has an impact on atherosclerotic plaques, we crossed LmnaL648R/L648R mice to LDL receptor-deficient Ldlr-/- mice that develop hyperlipidemia on a high-fat diet. RESULTSAtherosclerotic plaque lesion area and necrotic core area were not different in hyperlipidemic LmnaL648R/L648R mice that expressed only prelamin A, and no mature lamin A, compared to hyperlipidemic Lmna+/+ mice that expressed only fully-processed mature lamin A and no prelamin A. Additionally, exclusive prelamin A expression did not result in loss of aortic VSMCs or adventitial thickening in hyperlipidemic LmnaL648R/L648R mice with atherosclerosis at 28 weeks of age. Indeed, aortic vascular smooth muscle remained normal in older LmnaL648R/L648R mice at 52 weeks of age. CONCLUSIONSIn contrast to the prelamin A variant progerin expressed in HGPS, prelamin A does not appear to cause vascular smooth muscle loss, promote atherosclerosis or drive vascular aging.