Research
Mechanisms of genes that cause coronary artery disease
Large human genetic studies have identified regions of the genome responsible for the development of coronary artery disease (CAD). We identify the causal genes in these regions and determine i) how they influence blood vessel biology during disease and ii) the molecular pathways they control. By starting with the most important genes driving clinical CAD, we maximize the potential of uncovering new treatments for this disease.
Transcriptional regulation of smooth muscle cells
During atherosclerosis, smooth muscle cells (SMCs) de-differentiate, proliferate and migrate into the lesion, eventually comprising up to 60% of all cells within the lesion. Underscoring the importance of this observation, human genetic studies of coronary artery disease (CAD) also point to SMCs as a critical mediator of disease risk. Understanding the transcriptional programs that govern this critical cellular transition opens up the possibility of intervening to modify disease risk.
Publications
Wirka RC, Wagh D, Paik DT, Pjanic M, Nguyen T, Miller CL, Kundu R, Nagao M, Coller J, Koyano TK, Fong R, Woo YJ, Liu B, Montgomery SB, Wu JC, Zhu K, Chang R, Alamprese M, Tallquist MD, Kim JB, Quertermous T. “Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis”. Nature Medicine, 2019 July 29. (8):1280-1289. PMID: 31359001
Pedroza AJ, TashimaY, Shad R, Cheng P, Wirka R, Churovich S, Nakamura K, Yokoyama N, Cui JZ, Iosef C, Hiesinger W, Quertermous T, Fischbein MP. “Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm” Arterioscler Thromb Vasc Biol., 2020 Sep; 40: 2195–2211. PMID: 32698686
Zhao Q, Dacre M, Nguyen T, Pjanic M, Liu B, Iyer D, Cheng P, Wirka R, Kim JB, Fraser HB, Quertermous T. “Molecular mechanisms of coronary disease revealed using quantitative trait loci for TCF21 binding, chromatin accessibility, and chromosomal looping”. Genome Biol., 2020 Jun 8; 21:135. PMCID: PMC7278146
Kim JB, Zhao Q, Nguyen T, Pjanic M, Cheng P, Wirka R, Travisano S, Nagao M, Kundu R, Quertermous R. “Environment-Sensing Aryl Hydrocarbon Receptor Inhibits the Chondrogenic Fate of Modulated Smooth Muscle Cells in Atherosclerotic Lesions”. Circulation, 2020 Aug 11; 142:575–590. PMID: 32441123
Rykaczewska U, Suur BE, Röhl S, Razuvaev A, Lengquist M, Sabater-Lleal M, van der Laan SW, Miller CL, Wirka RC, Kronqvist M, Gonzalez Diez M, Vesterlund M, Gillgren P, Odeberg J, Lindeman JH, Veglia F, Humphries SE, de Faire U, Baldassarre D, Tremoli E; IMPROVE study group, Lehtiö J, Hansson GK, Paulsson-Berne G, Pasterkamp G, Quertermous T, Hamsten A, Eriksson P, Hedin U, Matic L “PCSK6 Is a Key Protease in the Control of Smooth Muscle Cell Function in Vascular Remodeling”. Circulation Research, 2020 Feb 28; 126(5):571-585. PMID 31893970
Flores AM, Hosseini-Nassab N, Jarr KU, Ye J, Zhu X, Wirka R, Koh AL, Tsantilas P, Wang Y, Nanda V, Kojima Y, Zeng Y, Lotfi M, Sinclair R, Weissman IL, Ingelsson E, Smith BR, Leeper NJ. “Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis”. Nat Nanotechnol. 2020 Feb 15; 15(2):154-161. PMID 31988506
Nagao M, Lyu Q, Zhao Q, Wirka RC, Bagga J, Nguyen T, Cheng P, Kim JB, Pjanic M, Miano JM, Quertermous T. “Coronary Disease-Associated Gene TCF21 Inhibits Smooth Muscle Cell Differentiation by Blocking the Myocardin-Serum Response Factor Pathway”. Circulation Research, 2020 Feb 14; 126(4):517-529. PMID 31815603
Zhao Q, Wirka R, Nguyen T, Nagao M, Cheng P, Miller CL, Kim JB, Pjanic M, Quertermous T. “TCF21 and AP-1 interact through epigenetic modifications to regulate coronary artery disease gene expression”. Genome Med. 2019 May 2. 11(1):23. PMCID 6480881
Iyer D, Zhao Q, Wirka R, Naravane A, Nguyen T, Liu B, Nagao M, Cheng P, Miller CL, Kim JB, Pjanic M, Quertermous T. “Coronary artery disease genes SMAD3 and TCF21 promote opposing interactive genetic programs that regulate smooth muscle cell differentiation and disease risk”. PLoS Genet. 2018 Oct 11;14(10):e1007681. PMID 30307970
Paik DT, Tian L, Lee J, Sayed N, Chen IY, Rhee S, Rhee JW, Kim Y, Wirka RC, Buikema JW, Wu SM, Red-Horse K, Quertermous T, Wu JC. “Large-Scale Single-Cell RNA-Seq Reveals Molecular Signatures of Heterogeneous Populations of Human Induced Pluripotent Stem Cell-Derived Endothelial Cells”. Circ Res. 2018 Jul 9. (4):443-450. PMID 29986945
Wirka RC, Pjanic M, Quertermous T. “Advances in Transcriptomics: Investigating Cardiovascular Disease at Unprecedented Resolution”. Circulation Research. 2018 Apr 27;122(9):1200-1220. PMID 29700068
Wirka RC, Quertermous T. “Circulating peptide prevents preeclampsia”. Science. 2017 Aug 18;357(6352):643-644. PMID 28818928
Xu B, Fu Y, Liu Y, Agvanian S, Wirka RC, Baum R, Zhou K, Shaw RM, Hong T. “The ESCRT-III pathway facilitates cardiomyocyte release of cBIN1-containing microparticles”. PLoS Biol. 2017 Aug 14;15(8). PMID 28806752
Pjanic M, Miller CL, Wirka R, Kim JB, DiRenzo DM, Quertermous T. “Genetics and genomics of coronary artery disease”. Curr Cardiol Rep. 2016(Oct 18). (10):102. PMID 27586139
Tchou GD, Wirka RC, Van Wagoner DR, Barnard J, Chung MK, Smith JD. “Low prevalence of connexin-40 gene variants in atrial tissues and blood from atrial fibrillation subjects”. BMC Med Genet, 2012(Nov 7). 13:102. PMID 23134779
Kim JJ, Vaziri SA, Rini BI, Elson P, Garcia JA, Wirka RC, Dreicer R, Ganapathi MK, Ganapathi R. "Association of VEGF and VEGFR2 Single Nucleotide Polymorphisms With Hypertension and Clinical Outcome in Metastatic Clear Cell Renal Cell Carcinoma Patients Treated With SunitinibAssociation of VEGF and VEGFR2 Single Nucleotide Polymorphisms With Hypertension and Clinical Outcome in Metastatic Clear Cell Renal Cell Carcinoma Patients Treated With Sunitinib". Cancer, 2011(Aug 31). 118(7):1946-54. PMID 21882181
Wirka RC, Gore S, Van Wagoner DR, Barnard J, Arking DE, Lubitz SA, Benjamin EJ, Alonzo A, Ellinor PT, Chung MK, Smith JD. " A Common Connexin-40 Gene Promoter Variant Affects Connexin-40 Expression in Human Atria and Is Associated with Atrial Fibrillation". Circulation Arrhythmia and Electrophysiology, 2010(Nov 13). 4(1):87-93. PMID 21076161