A wrinkle in time: circadian biology in pulmonary vascular health and disease

Abstract

An often over looked element of pulmonary vascular disease is time. Cellular responses to time, which are regulated directly by the core circadian clock, have only recently been elucidated. Despite an extensive collection of data regarding the role of rhythmic contribution to disease pathogenesis (such as systemic hypertension, coronary artery and renal disease), the roles of key circadian transcription factors in pulmonary hypertension remain under-studied. This is despite a large degree of overlap in the pulmonary hypertension and circadian rhythm fields, including not only shared signaling pathways, but also cell-specific effects of the core clock that are known to result in both protective and adverse lung vessel changes. Therefore, the goal of this review is to summarize the current dialogue regarding common pathways in circadian biology, with a specific emphasis on its implications in the progression of pulmonary hypertension. In this work, we emphasize specific proteins involved in the regulation of the core molecular clock while noting the circadian cell-specific changes relevant to vascular remodeling. Finally, we apply this knowledge to the optimization of medical therapy, with a focus on sleep hygiene and the role of chronopharmacology in patients with this disease. In dissecting the unique relationship between time and cellular biology, we aim to provide valuable insight into the practical implications of considering time as a therapeutic variable. Armed with this information, physicians will be positioned to more efficiently utilize the full four dimensions of patient care, resulting in improved morbidity and mortality of pulmonary hypertension patients.

Mitochondrial Dynamics in Pulmonary Hypertension

“…Through the action of tobacco smoke on lung parenchyma cell rhythms, it stands to reason that the pulmonary vasculature would also have a specific change at the tissue level at the clock output in response to exposure to inhalants, temperature, hypoxia, etc. [29]. Incidentally, it has recently been shown that circadian transcriptomic changes in hypoxic lung immune cells are very similar to those in patients with PH [69].…”

“…Although the role of the circadian clock has been well described in the progression of chronic airway diseases after exposure to nicotine, interruption of the circadian cycle has not been associated with pulmonary vascular remodeling, resulting in PH [29]. Unfortunately, little is known about the circadian variability that directly contributes to PH, despite the interest in intact lung effects [30].…”

“…REV-ERBα is known to suppress CCL2 chemokine expression by cells of the monocyte/macrophage lineage [29], which are known to be both necessary and sufficient for the development of hypoxia-mediated PH [51] through the native CCR2 receptor [52]. Likewise, REV-ERBα directly binds to the IL6 promoter region and indirectly affects NF-κB binding motif to inhibit IL-6 signaling [53], which is considered to have a protective effect in patients with PH [54].…”

“…Furthermore, hypoxia increases the expression of the circadian genes PER1 and CLOCK in the mouse brain, modulating the circadian clock at the molecular level, probably via affecting HIF-1 signaling [38]. Through the action of tobacco smoke on lung parenchyma cell rhythms, the pulmonary vasculature would also have a specific change at the tissue level at the clock output to further response to hypoxia [29]. Noticeably, circadian transcriptomic changes in hypoxic lung immune cells are very similar to those in patients with PH [69].…”

KAT’s in the Cradle: p300/CBP and Regulation of HIF-1 and Blood Pressure during Intermittent Hypoxia

“…Moreover, the sympathetic nervous system and systemic circulation are not the only targets of IH. Recent work by Mesarwi and colleagues ( 12 ) showed that both HIF-1 and IH promote nonalcoholic fatty liver disease in a mouse model, while IH induced oxidant stress and enhanced pulmonary vasoreactivity in rats ( 13 ) and may disrupt the circadian clock ( 14 ), potentially contributing to pulmonary hypertension. The broader applicability of CTK7A to noncardiovascular IH-driven events remains to be tested.…”