The human smooth muscle myosin heavy chain is the target of mutations that can cause familial thoracic aortic aneurysm dissection (TAAD). The underlying irnpact of the mutations is unknown, but it has been speculated that the mutations cause decreased force output in the smooth muscle cells. Intriguingly, mutations in similar regions of the human smooth muscle myosin have been associated with colorectal (CR) cancer, while other mutations are associated with intracranial aneurysms (ICA). In the case of the cancer- associated mutations, features shared with the TAAD-causing mutations that we have examined to date are a loss of regulation and altered kinetics that are consistent with decreased force output. We hypothesize that that a critical feature of the TAAD mutations that leads to disease is the loss of regulation. We hypothesize that the ICA-associated mutations will have a differential impact that will distinguish them from the TAAD- causing mutations. This likely will be altered contractile function without any loss of regulation. This will allow us to develop diagnostic evaluations of protein function that may prove of predictive value as to the consequences of mutations detected in patients prior to disease onset. This proposal makes use of our ability to express large amounts of human smooth muscle myosin in SF9 cells. We will characterize the impact of TAAD and ICA mutations on the kinetics, motility and regulation of human smooth muscle myosin, as well as examine filament forming properties and the impact on force generation at the ensemble and single molecule level for a subset of the mutations.

Public Health Relevance

A number of genes have been linked to thoracic aortic aneurysms leading to type A dissections (TAAD). This project seeks to study the effect of the mutations in myosin in sufficient detail to allow an understanding of the pathological processes that takes place, which in turn could lead to new insights and better treatments for the diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center Houston
United States
Zip Code
Milewicz, Dianna M; Regalado, Ellen S; Shendure, Jay et al. (2014) Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections. Trends Cardiovasc Med 24:53-60
Kwartler, Callie S; Chen, Jiyuan; Thakur, Dhananjay et al. (2014) Overexpression of smooth muscle myosin heavy chain leads to activation of the unfolded protein response and autophagic turnover of thick filament-associated proteins in vascular smooth muscle cells. J Biol Chem 289:14075-88
Qiao, Yan-Ning; He, Wei-Qi; Chen, Cai-Ping et al. (2014) Myosin phosphatase target subunit 1 (MYPT1) regulates the contraction and relaxation of vascular smooth muscle and maintains blood pressure. J Biol Chem 289:22512-23
Regalado, Ellen S; Guo, Dong-chuan; Estrera, Anthony L et al. (2014) Acute aortic dissections with pregnancy in women with ACTA2 mutations. Am J Med Genet A 164A:106-12
Tsai, Ming-Ho; Chang, Audrey N; Huang, Jian et al. (2014) Constitutive phosphorylation of myosin phosphatase targeting subunit-1 in smooth muscle. J Physiol 592:3031-51
Nelson, Michael D; Rader, Florian; Tang, Xiu et al. (2014) PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. Neurology 82:2085-91
Guo, Dong-chuan; Regalado, Ellen; Casteel, Darren E et al. (2013) Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet 93:398-404
Gao, Ning; Huang, Jian; He, Weiqi et al. (2013) Signaling through myosin light chain kinase in smooth muscles. J Biol Chem 288:7596-605
Kuang, Shao-Qing; Geng, Liang; Prakash, Siddharth K et al. (2013) Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade. Arterioscler Thromb Vasc Biol 33:2172-9
Barua, Bipasha; Fagnant, Patricia M; Winkelmann, Donald A et al. (2013) A periodic pattern of evolutionarily conserved basic and acidic residues constitutes the binding interface of actin-tropomyosin. J Biol Chem 288:9602-9

Showing the most recent 10 out of 12 publications