Research in the Walsh laboratory investigates the signaling- and transcriptional-regulatory mechanisms that control both normal and pathological tissue growth in the cardiovascular system. Our studies were among the first to document that the eNOS/PI3-kinase/Akt/GSK/Forkhead signaling axis is of critical importance in the regulation of the cardiovascular system. Signaling through this pathway controls cellular enlargement (hypertrophy), cell death (apoptosis), and blood vessel recruitment and growth (angiogenesis). We have shown that the PI3-kinase/Akt/eNOS/GSK/Forkhead signaling axis regulates multiple steps critical in angiogenesis including endothelial cell apoptosis, differentiation, nitric oxide production and migration. We have also shown that some of these signaling steps are important for cardiac hypertrophy during normal postnatal development and that they regulate myocyte survival in models of heart disease.
Major projects in the Walsh laboratory have analyzed mechanisms of inter-tissue communication within the cardiovascular system and how these regulatory mechanisms are perturbed by obesity-induced metabolic dysfunction. Using mouse genetic models we found that perturbations in crosstalk mechanisms between cardiac myocytes and vascular endothelial cells contribute to the transitions from compensated hypertrophy to heart failure. Factors involved in this regulation include VEGF, Fstl1, Fstl3 and Activin-A. Subsequent studies in patient populations have shown that at least one of these factors (Fstl1) is upregulated in clinical heart failure and is predictive of mortality in patients with acute coronary syndrome. Related studies have examined how alterations in the expression of adipocyte-derived cytokines, referred to as adipokines, interfere with normal signaling within the cardiovascular system and thereby contribute to cardiovascular disease. Adiponectin is an anti-inflammatory adipokine that is down-regulated in obesity. Studies by the Walsh laboratory were the first to show that adiponectin directly acts on the heart and vasculature as a cardio-protective factor. More recently we found that the Sfrp5/Wnt5a regulatory axis functions to control systemic metabolism through regulation of adipose tissue inflammation. Finally, the laboratory has examined how age-associated loss of skeletal muscle mass affects metabolic and cardiovascular function, and is exploring the possibility that muscle-secreted factors (myokines) confer some of the benefits of exercise training on cardiovascular and metabolic diseases.
A new project in the laboratory investigates how acquired mutations in blood cells contribute to the development of cardiovascular disease. Somatic DNA mutations accumulate over time in many tissues, and this is a hallmark of the aging process. In particular, somatic mutations in preleukemic “driver” genes within hematopoietic stem cells can confer “fitness” advantages leading to the clonal amplification of these cells. This process is referred to as clonal hematopoiesis, and it is remarkably prevalent in the elderly population. A number of recent studies have associated advanced clonal hematopoiesis with increased mortality and elevated risk of cardiovascular disease and stroke. Using the epigenetic regulator Tet2 as a test case, investigations in our lab provided the first mechanistic framework in support of the hypothesis that these somatic mutations represent a new causal risk factor for cardiovascular disease. This line of investigation has provided support for a new paradigm of inflammation-mediated cardiovascular disease that is summarized by our recent papers.
For the most current list of Walsh Lab publications, please click here.
Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice. J.J. Fuster, et al. (2018). Science 355:842-847. PMCID: PMC5542057. Accompanied by Perspective, Science; News Feature in Science; News and Views in Nature; Research Highlights in Nature, Nature Immunology and Nature Reviews Drug Discovery; Editor’s choice, Science Signaling, Year in Review, Nature Reviews, Cardiology.
Tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the IL-1β/NLRP3 inflammasome. S. Sano et al. (2017). J. Am. Coll. Cardiol. 71:875-886. PMCID: PMC5828038. Accompanied by editorial; Research Highlight in Nature Reviews, Cardiology.
Invited Emerging Science Review: “Somatic mutations and clonal hematopoiesis: Unexpected potential new drivers of age-related cardiovascular disease”. J. J. Fuster, K. Walsh (2018). Circ. Res. 122:523-532. PMCID: PMC5826570.
CRISPR-mediated gene editing to assess the roles of Tet2 and Dnmt3a in clonal hematopoiesis and cardiovascular disease. S. Sano et al. (2018). Circ. Res. 123:335-341. PMCID: PMC6054544.