Biochemistry, Cardiovascular Biology, Metabolism
The role of clonal hematopoiesis in cardio-metabolic disease processes
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. These studies 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 analyze 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, they have 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 on inter-tissue communication 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 downregulated in obesity. Studies by the Walsh laboratory were first to show that adiponectin directly acts on the heart and vasculature as a cardio-protective factor. More recently, the Walsh laboratory reported that the non-canonical Sfrp5/Wnt5a regulatory axis functions to control systemic metabolism through regulation of adipose tissue inflammation, with impacts on cardio-metabolic disease. Related to these studies, the Walsh 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.
More recently, the Walsh laboratory has performed seminal investigations into the role that clonal hematopoiesis has in cardio-metabolic disease processes. There has long been debate that the traditional, modifiable risk factors (hyperlipidemia, hypertension, diabetes and smoking), all established more than 50 years ago, are incompletely predictive of cardiovascular disease (CVD). Furthermore, there is a poor understanding of how aging, the major CVD risk factor, promotes disease progression. Somatic DNA mutations accumulate with age in many tissues, leading to genomic mosaicism. However, the causal role of genomic mosaicism in the diseases of the elderly other than cancer is relatively unexplored. Large exome sequencing studies in humans have shown that aging is associated with an increased frequency of somatic mutations in the hematopoietic system that provide a competitive growth advantage to the mutant cell and therefore allow its clonal expansion (i.e. clonal hematopoiesis). Unexpectedly, these somatic mutations have been found to be associated with greater risk of coronary heart disease and stroke, suggesting a previously unrecognized link between somatic mutations in the hematopoietic system and CVD. One of the genes that is frequently mutated in clonal hematopoiesis is the epigenetic regulator Tet2. Using Tet2 as a test case, the Walsh laboratory explored whether the expansion of mutant hematopoietic cells promotes atherosclerosis and heart failure mice. The findings from these related studies support the concept that clonal hematopoiesis due to somatic mutations represents a new mechanism of CVD that shares features with hematologic malignancy. Further research in the area of hemato-vascular biology could provide a mechanistic framework for the development of personalized medicines for CVD that are tailored for individuals that carry specific somatic mutations in their hematopoietic cells.