MSGID: 1:317/3 64a8e681   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    How a genetic mutation can cause individuals with normal cholesterol   
   levels to develop coronary artery disease at a young age    
      
     Date:   
         July 7, 2023   
     Source:   
         University of Texas Health Science Center at Houston   
     Summary:   
         A novel molecular pathway to explain how a mutation in the gene   
         ACTA2 can cause individuals in their 30s -- with normal cholesterol   
         levels and no other risk factors -- to develop coronary artery   
         disease has now been identified,.   
      
      
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   A novel molecular pathway to explain how a mutation in the gene ACTA2   
   can cause individuals in their 30s -- with normal cholesterol levels   
   and no other risk factors -- to develop coronary artery disease has been   
   identified, according to researchers with UTHealth Houston.   
      
   The study was published in the European Heart Journal.   
      
   "The gene ACTA2 codes a specific protein that has nothing to do with   
   cholesterol," said Dianna Milewicz, MD, PhD, senior author of the study   
   and professor and director of the Division of Medical Genetics at McGovern   
   Medical School at UTHealth Houston. "It was a surprise to find that   
   people with the gene mutation had too much atherosclerosis at a young   
   age and with no risk factors."  A 2009 study led by Milewicz found that   
   a number of mutations in ACTA2 predispose humans to develop early onset   
   (30s or younger) coronary artery disease.   
      
   Atherosclerosis is a buildup of fats, cholesterol, and other substances   
   in and on the artery walls. It can develop over time and most people don't   
   know they have it until they suffer a heart attack or stroke. Traditional   
   risk factors for developing atherosclerosis include high cholesterol,   
   high blood pressure, diabetes, smoking, obesity, lack of exercise,   
   and consuming a high-fat diet.   
      
   ACTA2 is typically found in the smooth muscle cells, which line the   
   arteries and allow the arteries to contract to control blood pressure   
   and flow. Milewicz and her team found that protein coded by this gene   
   is not folded correctly because of the mutation, and it triggers stress   
   in the smooth muscle cell, which then forces the cell to make more   
   cholesterol internally, regardless of the levels of cholesterol in the   
   blood, driving atherosclerotic plaque formation.   
      
   "This finding is unique in that we found a completely new pathway to   
   atherosclerosis. It explains why for years we have known statins protect   
   people from heart attacks, even those people whose blood cholesterol   
   levels are normal. In the people with ACTA2 mutations, the statins block   
   the cholesterol made by the stressed smooth muscle cells," said Milewicz,   
   the President George Bush Chair in Cardiovascular Medicine with McGovern   
   Medical School. "In our study, the mutant protein made by the ACTA2   
   mutation caused the cells in the artery wall to be stressed, but there   
   are many other factors that can stress cells. We are now working on the   
   risk factors for coronary artery disease, like hypertension, that would   
   also stress the cells and activate this novel pathway for coronary artery   
   disease."  One of the results of stress in smooth muscle cells associated   
   with atherosclerosis is the deposition of calcium in the arteries.   
      
   "Cardiac calcium imaging in individuals with ACTA2 mutations could be   
   a useful early diagnostic tool to monitor the development of the early   
   atherosclerosis in these people. This would allow physicians to decide   
   at what age to start these patients on statins," Milewicz said.   
      
   Using a genetically engineered mouse that contains a particular   
   ACTA2 mutation and feeding the mice a diet rich in cholesterol, the   
   researchers induced atherosclerosis and found that these mice have   
   much more atherosclerosis than similarly treated mice normal mice. The   
   study also found that the increased atherosclerosis could be reversed   
   by treating the mice with pravastatin, a member of the statin group of   
   drugs commonly prescribed to lower blood cholesterol. The researchers   
   confirmed that same molecular pathway is activated in smooth muscles   
   cells isolated from a human patient with an ACTA2 mutation.   
      
   Statins prevent coronary artery disease by lowering the levels of   
   cholesterol in the blood. At the same time, more than half of heart   
   attacks occur in apparently healthy men and women with average or low   
   levels of plasma LDL- cholesterol. Statins also reduce heart attack   
   events in people with normal cholesterol levels.   
      
   This work was supported by the National Heart, Lung, and Blood   
   Institute (RO1 HL146583); an America Heart Association Merit Award,   
   NIH T32GM120011; Marfan Foundation McKusick Fellowship Award; and   
   American Heart Association Grant 20CDA35310689. Lipid profile analysis   
   was performed at the Mouse Metabolism and Phenotypic Core at Baylor   
   College of Medicine, funded by NIH RO1DK114356 and UM1HG006348. Single   
   cell RNA sequencing was performed at the Single Cell Genomics Core at   
   Baylor College of Medicine, funded by National Institutes of Health   
   shared instrument grants S10OD023469, S10OD025240 and P30EY002520.   
      
   Additional UTHealth Houston authors include Kaveeta Kaw, MD, PhD; Abhijnan   
   Chattopadhyay, PhD; Pujun Guan, MM; Jiyuan Chen, PhD; Suravi Majumder,   
   PhD; Xue-yan Duan, PhD, and Callie S. Kwartler, PhD. Other authors   
   include Shuangtao Ma, MD, MSc, with Michigan State University College   
   of Human Medicine (a former postdoctoral fellow at UTHealth Houston)   
   and Chen Zhang, MD, with Baylor College of Medicine.   
      
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   Original written by Jeannette Sanchez. Note: Content may be edited for   
   style and length.   
      
      
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   Journal Reference:   
      1. Kaveeta Kaw, Abhijnan Chattopadhyay, Pujun Guan, Jiyuan Chen, Suravi   
         Majumder, Xue-yan Duan, Shuangtao Ma, Chen Zhang, Callie S Kwartler,   
         Dianna M Milewicz. Smooth muscle a-actin missense variant promotes   
         atherosclerosis through modulation of intracellular cholesterol   
         in smooth muscle cells. European Heart Journal, 2023; DOI:   
         10.1093/eurheartj/ ehad373   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230707124650.htm   
      
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