Obstructive Sleep Apnea (OSA) is a complete or partial airway obstruction that causes significant physiological disturbances. While patients commonly experience snoring, nocturnal awakening, and daytime sleepiness, one of the most severe clinical characteristics linked to OSA severity is hypertension [1].
A key pathological mechanism driving this cardiovascular risk in OSA patients is Chronic Intermittent Hypoxia (CIH), which is known to induce cardiac dysfunction [2].
The carotid body (CB) plays a critical, central role in CIH-induced hypertension. As a major regulator of sympathetic nerve activity, the carotid body becomes hyper-sensitized by CIH, dramatically increasing its sensory nerve response to acute hypoxia.
Previous studies have shown a direct causal pathway: when the carotid body is ablated in rodent models, CIH-induced sympathetic nerve activation and the resulting hypertension are entirely prevented [3]. This indicates that CIH-related activation of the carotid body acts as the underlying trigger that chronically activates the sympathetic nervous system, ultimately leading to hypertension in OSA patients.
To better understand the specific molecular mechanisms of the carotid body in CIH-induced hypertension, Dr. Peng’s research team at the University of Chicago focused on an olfactory receptor known as Olfr78.
Expressed in murine carotid bodies, knocking out Olfr78 was shown to impair the carotid body’s response to acute hypoxic exposure. The team expanded their research by investigating the hemeoxygenase 2 (HO-2) enzyme,a carbon dioxide catalyzer. Because HO-2 null mice exhibit spontaneous apneic episodes during sleep, the researchers used them to test whether the carotid body sensory nerve response to hypoxia was amplified in the same way it is in CIH-treated mice.
After exposing Olfr78 null mice to CIH, Dr. Peng’s team uncovered critical insights into how this receptor influences cardiovascular and respiratory health:
Blood Pressure and Heart Rate: CIH successfully increased both blood pressure and heart rate in wild-type (WT) mice, but not in Olfr78 null mice.
Breathing Stability: Using a Whole-Body Plethysmography system, the team measured apneic episodes across different genetic models.
HO-2 null mice exhibited highly irregular breathing patterns, experiencing an average of 58 ± 1.2 apneas/hour.
HO-2/Olfr78 double null mice maintained relatively stable breathing, experiencing only 12 ± 1.3 apneas/hour.
Sensory Response: HO-2 null mice displayed an enhanced carotid body sensory response to acute hypoxia. This amplified response was completely absent in the HO-2/Olfr78 double null mice.
These findings provide strong evidence that the Olfr78 receptor actively participates in carotid body-dependent sympathetic nerve activation and hypertension across two distinct mouse models of CIH.
By pinpointing the specific receptors and pathways driving elevated blood pressure, this data significantly improves our comprehension of the complex pathological mechanisms involved in Obstructive Sleep Apnea, potentially paving the way for targeted cardiovascular therapies in the future.
After exposing Olfr78 null mice to CIH, Dr. Peng’s team found that CIH increases blood pressure and heart rate in wild-type (WT) but not in Olfr78 null mice. Furthermore, apneic episodes per hour were measured in WT, HO-2, and HO-2/Olfr78 double null mice using the Whole-Body Plethysmography system. These measurements helped highlight that HO-2 null mice breathing patterns were irregular (58 ± 1.2 apneas/hour) compared to HO-2/Olfr78 double null mice with a relatively stable breathing (12 ± 1.3 apneas/hour). Additionally, HO-2 null mice showed enhanced carotid body sensory response to acute hypoxia and this effect was absent in HO-2/Olfr78 double null mice. Therefore, these current results do suggest evidence for Olfr78 participation in carotid body-dependent sympathetic nerve activation and hypertension in two mice models of CIH. This data might help improve our comprehension on the complex pathological mechanisms involved in OSA.
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