Naira is a rising senior at New Jersey Institute of Technology where she studies biology. She works in Dr. Assoian’s Pharmacology lab, which studies the mechanobiology of aging and its relation to cardiovascular diseases, particularly atherosclerosis. The lab has also taken interest in Hutchinson- Gilford Progeria syndrome (HGPS), which serves as a model for vascular aging. In particular, Naira’s project focuses on characterizing the altered mechanotransduction of vascular smooth muscle cells in the arteries of mice with HGPS.
Molecular mechanisms regulating arterial stiffness in Hutchinson-Gilford Progeria Syndrome
Hutchinson- Gilford Progeria syndrome (HGPS) is a rare autosomal genetic disorder characterized by premature aging in children and death by accelerated cardiovascular disease (CVD). Blood cholesterol levels are normal in HGPS children, but their arteries are abnormally stiff. Arterial stiffness is a major cholesterol-independent risk factor for CVD. Arterial stiffening is characterized by increased ECM production by vascular smooth muscle cells (vSMCs) of the arterial medial layer. vSMCs can exist in a contractile (differentiated) state, characterized by expression of differentiation markers such as smooth muscle myosin heavy chain (Myh11), and a synthetic (dedifferentiated) state that produces ECM and ECM-modifying proteins such as lysyl oxidase (LOX). Using an HGPS- mouse model, we have previously shown that decreased mRNA expression of Myh11 in HGPS-SMCs correlates with increased LOX expression. Here, we examine the role of Myh11 in regulating LOX production and explore the role of endothelium-derived nitric oxide (NO) in arterial stiffness. Knockdown of Myh11 in WT-vSMCs increased LOX mRNA expression, suggesting that reduced Myh11, in the absence of genetic variables intrinsic to HGPS-vSMCs, is sufficient to increase LOX levels. As recent studies by others have shown that NO is a regulator of Myh11, we also explored the role of eNOS and NO in Myh11 and Lox regulation. RT-qPCR showed that Nos3 expression is significantly downregulated in HGPS-arteries. Moreover, addition of an exogenous NO donor to isolated HGPS-vSMCs increased Myh11 and decreased LOX gene expression. Our results indicate that nitric oxide may regulate SMC phenotype and identify defective NO signaling as a potential mediator of arterial stiffness in HGPS.