Niranjana Natarajan, Ph.D.

Cardiovascular disease (CVD) is the leading cause of mortality in the developed world and contributes to 1/3rd of all-cause mortality in the United States. Heart failure is the end stage clinical manifestation of a multitude of cardiovascular diseases, characterized by extensive cardiac fibrosis, adverse remodeling, impaired function and inability of the heart to pump sufficient amounts of blood into circulation during systole. Chronic, unresolved inflammation mediates cardiac and renal tissue damage in heart failure. Macrophages are the primary innate immune cells in the heart, and undergo expansion in CVD. My research focuses on understanding the factors that regulate immune activation and promote inflammation in CVD. To this end, below I describe my research interests.

Direction 1: Innate immune signaling in the pathology of Heart Failure with Preserved Ejection Fraction (HFpEF)

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome that presents with heart failure (HF) symptoms and unaltered left ventricular ejection fraction. HFpEF patients suffer from multiple co-morbidities such as hypertension diabetes, renal disease, obesity and metabolic syndrome. Our work takes a novel integrated systems biology perspective to understand inflammatory signaling in HFpEF and identify novel targets for immunomodulation. Our work shows that inflammatory cell infiltration is associated with an increase in fibroblast differentiation, extracellular matrix (ECM) biosynthesis pathways, and expression of ECM genes in the heart. Given the crucial role played by macrophages in cardiac function and CVD, we hypothesize that systemic inflammation increases macrophage infiltration into the heart, which in turn results in pathological signaling events that cause cardiac remodeling in HFpEF. We are focused on mechanisms of myofibroblast activation and pathological cardiac remodeling by macrophages at the: (i) functional level, (ii) cellular level and (iii) molecular level using a 2-hit HFpEF model.

Complement signaling mediated inflammation in HFpEF. Complement receptors play an important role in the recruitment of inflammatory cells to the heart in CVD. We observe upregulation of C1q, C3 and its receptor C3aR in cardiac macrophages in the murine HFpEF models. Therefore, we will focus on the pathological role of complement activation in cardiac remodeling and diastolic dysfunction in HFpEF.

Direction 2: Epigenetic regulation by microbe-to-host signaling in cardiovascular disease

We are interested in exploring microbe-to-host signaling networks that regulate inflammation and macrophage function. Epigenetic processes play a key role in modulating macrophage polarization and inflammatory gene expression. Short chain fatty acids (SCFA) and TCA intermediates produced by the commensal microbiome exhibit histone deacetylase (HDAC) activity, and succinate, fumarate and 2-hydroxyglutarate inhibit the JmjC histone demethylases. Individuals with obesity, hypertension and metabolic syndrome, common comorbidities associated with cardiovascular disease (CVD), exhibit altered commensal microbiota composition. Here, we are focused on the contribution of commensal microbiota to macrophage polarization and epigenetic regulation. Using a combination of animal models, cell culture and multi-omic approaches, we are exploring alterations in the epigenetic state of leukocytes and macrophages in obese, hypertensive and CVD patients.

Microbiome mediated trained immune memory. Increased inflammation in CVD is mediated by an increased hematopoietic supply of immune cells. The hematopoietic niche is considerably altered by obesity, inflammation, diabetes and hypertension, common comorbidities in patients with CVD. Previously, we showed that processed diet with high sugar and fat increases cardiac fibrosis and rewires cardiac metabolism in mice. We are building on this work and address dysbiosis-induced transcriptomic and epigenetic changes in hematopoietic stem and progenitor cells, circulating, tissue resident myeloid cells and leukocytes.

Direction 3: Chemosensory GPCRs in macrophage polarization and function

G-protein coupled receptors comprise the largest gene family in the human and murine genome. Our work has identified GPCRs for short and medium chain fatty acids to play important roles in regulating macrophage polarization, inflammatory response and function. Here, we are interested in understanding the function of SCFA / MCFA GPCRs in macrophage biology and in the context of heart failure.