Targeting Tyrosine Hydroxylase for Abdominal Aortic Aneurysm: Impact on Inflammation, Oxidative Stress, and Vascular Remodeling

Abstract

Pharmacological treatments for preventing abdominal aortic aneurysm (AAA) rupture or slowing aneurysm progression remain a challenge. It is increasingly recognized that sympathetic activity might play a role in the pathogenesis of AAA; however, the impact of this pathway remains unclear. Here, we show that the expression of tyrosine hydroxylase ( TH ), dopamine β-hydroxylase ( DBH ), and the norepinephrine transporter SLC6A2 is upregulated in abdominal aorta samples from AAA patients and in the aneurysmal aorta from 2 animal models susceptible to Ang II (angiotensin II)–induced AAA: the apolipoprotein E-deficient (ApoE −/− ) model and a transgenic mouse that overexpresses the human nuclear receptor NOR-1 (neuron-derived orphan receptor-1) in the vascular wall (TgNOR-1 VSMC ). TH localizes to sympathetic nerves innervating the local vasculature, but also to inflammatory cells, and scattered vascular smooth muscle cell in human and mouse AAA. Interestingly, the preventive effect of doxycycline on AAA formation in Ang II–treated TgNOR-1 VSMC mice was associated to the normalization of vascular Th expression. Moreover, the TH specific inhibitor α-methyl- p -tyrosine protected against Ang II–induced AAA formation, limiting the progressive increase in aortic diameter without affecting blood pressure. The drug normalized MMP2 (matrix metalloproteinase 2) expression and MMP activity, preserving elastin integrity, attenuated the Ang II–mediated rise in vascular oxidative stress and inflammatory markers and reduced the inflammatory infiltrate. Finally, NOR-1, whose expression correlated with that of TH in human AAA, was able to drive human TH transcriptional activity in transient transfection assays. Therefore, the upregulation of the TH pathway could be critical in the pathophysiology of AAA, supporting the potential of pharmacological strategies targeting TH for AAA management.

CD69-oxLDL ligand engagement induces Programmed Cell Death 1 (PD-1) expression in human CD4 + T lymphocytes

“…Abdominal aortic samples were collected from patients undergoing open repair surgery for abdominal aortic aneurysm at the Hospital de la Santa Creu i Sant Pau (Barcelona, Spain) and from multi-organ donors [ 18 ]. The study was approved by the Ethics Committee of the Hospital de la Santa Creu i Sant Pau (Barcelona, Spain) and was conducted in accordance with the Declaration of Helsinki.…”

Metabolomics of Arterial Stiffness

“…Circulating Tyr is associated with insulin resistance [ 161 ] and can affect BCAA levels, since they compete for the same AA transporter for cellular uptake [ 162 ]. Recently, inhibition of Tyr hydroxylase, a rate-limiting enzyme of catecholamine biosynthesis, preserved elastin integrity, attenuated vascular OxS, and reduced the inflammatory infiltrate in mice [ 163 ]. Thus, this enzyme could serve as a potential therapeutic target for AS.…”

“…While some progress has already been made in determining therapeutic targets for AS, metabolomics research could further contribute to this endeavor. As reviewed above, the current more intriguing candidate metabolic modulators to improve AS include L-carnitine [ 64 ] and Tau [ 195 ] supplements, TMA-lyase inhibitors [ 72 ], PPARβ/δ activators [ 95 ], Tyr hydroxylase inhibitors [ 163 ], ceramide synthase inhibitors [ 141 ], SMS2 inhibitors [ 141 ], and direct AGE inhibitors [ 207 ].…”

NR4A3: A Key Nuclear Receptor in Vascular Biology, Cardiovascular Remodeling, and Beyond

“…This category encompasses genes encoding for enzymes involved in the biosynthesis of catecholamines such as tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) [ 78 ]. The enhanced expression of TH and DBH was further detected in aneurysmal lesions from the Ang II-infused ApoE −/− mouse model and, more importantly, in human aneurysmal samples, in which TH expression is more than 100 times higher than that of healthy aortas and correlates with NOR-1 mRNA levels [ 79 ]. TH expression localized mainly in peripheral sympathetic nerves innervating the vascular wall (GAP43+ cells), infiltrated lymphocytes (CD3+ cells), and scattered medial VSMC (SM α-actin+ cells).…”