Charles J. Lowenstein, M.D.
Chief, Department of Medicine, Cardiology
Director - Aab Cardiovascular Research Institute
Paul N. Yu Professorship in Cardiology - Department of Medicine, Cardiology
Professor - Department of Medicine, Cardiology
1986 | M.D. | Medicine | Harvard Medical School
1982 | B.S. | Biochemistry | Harvard University
My lab studies fundamental and clinical mechanisms of vascular inflammation and thrombosis that contribute to diseases such as pulmonary embolism, myocardial infarction, and stroke.
Venous thromboembolism (VTE) is a major cause of morbidity and mortality, with an annual incidence of over 900,000 in the USA. Elevated plasma levels of Von Willebrand factor (VWF) are a risk factor for venous thrombosis, but the genetic factors that regulate VWF levels are not well understood.
We use human genetics to discover new regulators of VWF levels. We are collaborating with the CHARGE Consortium of genetic epidemiologists to characterize the function of novel genetic variants that are linked to altered VWF levels in humans. For example, the CHARGE consortium performed genome wide association studies to show that mutations in the gene encoding STXBP5 are linked to altered VWF levels. Our team then explored the role of SXTBP in mice and in human endothelial cells. We discovered that STXBP5 is a novel regulator of endothelial release of VWF (Lowenstein JCI2014 and also Lowenstein ATVB2017).
Figure: Endothelial cells grown on a defined matrix
express granules containing VWF (red).
We also use human genetics to discover new regulators of platelet biology. We collaborate with the CHARGE Consortium and the INVENT Consortium, which recently identified more than 10 novel genes that are linked to excess pulmonary embolism in humans. We are now using functional tests to validate these candidate genes and discover new pathways in platelet biology and thrombosis. We have characterized one of these genes, SCL44A2, and its role in platelets. We discovered that SLC44A2 is a novel choline transporter needed for proper metabolism and function of platelets. Thus human genetics has revealed a novel metabolic pathway in platelets that causes thromboembolic disease.
Our approaches will increase our understanding of endothelial and platelet pathways that increase the risk of diseases such as venous thromboembolism, and they will identify new therapeutic targets for the prevention and treatment of thromboembolic diseases.
The Lowenstein Lab collaborates closely with the Morrell Lab and the Cameron Lab, all shown above.
- Zhu Q… and Lowenstein CJ, Novel Thrombotic Function of a Human SNP in STXBP5 Revealed by CRISPR/Cas9 Gene Editing in Mice. Arterioscler Thromb Vasc Biol. 2017 Feb;37(2):264-270.
- Miano J… and Lowenstein CJ, A CRISPR Path to Engineering New Genetic Mouse Models for Cardiovascular Research., Arterioscler Thromb Vasc Biol. 2016 Jun;36(6):1058-75.
- Zhu Q… and Lowenstein CJ, SNAP23 Regulates Endothelial Exocytosis of von Willebrand Factor., PLoS One.2015 Aug 12;10(8):e0118737.
- Zhu Q… and Lowenstein CJ. Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion. J Clin Invest. 2014 Oct;124(10):4503-16.
- Ito T… and Lowenstein CJ. Thioredoxin increases exocytosis by denitrosylating N-ethylmaleimide sensitive factor. J Biol Chem. 2011 Apr 1;286(13):11179-84
- Morrell CN… and Lowenstein CJ. Glutamate Mediates Platelet Activation Through the AMPA Receptor. J. Exp. Med. 2008 Mar 17;205(3):575-84.
- Matsushita K…. and Lowenstein CJ. Nitric Oxide Regulation of Exocytosis by S-Nitrosylation of N-ethylmaleimide Sensitive Factor. Cell 2003 Oct 17; 115(2): 139-150.