L-Citrulline Supplementation Reduces Blood Pressure and Myocardial Infarct Size under Chronic Intermittent Hypoxia, a Major Feature of Sleep Apnea Syndrome

Abstract

Intermittent hypoxia (IH) is a landmark of obstructive sleep apnea (OSA) at the core of the cardiovascular consequences of OSA. IH triggers oxidative stress, a major underlying mechanism for elevated blood pressure (BP) and increased infarct size. L-citrulline is an amino acid that has been demonstrated to be protective of the cardiovascular system and exert pleiotropic effects. Therefore, we tested the impact of citrulline supplementation on IH-induced increase in BP and infarct size. Four groups of rats exposed to normoxia (N) or IH [14 days (d), 8 h/day, 30 s-O2 21%/30 s-O2 5%] and were supplemented or not with citrulline (1 g·kg−1·d−1). After 14 d, BP was measured, and hearts were submitted to global ischemia-reperfusion to measure infarct size. Histological and biochemical analyses were conducted on hearts and aorta to assess oxidative stress. Citrulline significantly reduced BP (–9.92%) and infarct size (–18.22%) under IH only. In the aorta, citrulline supplementation significantly decreased superoxide anion and nitrotyrosine levels under IH and abolished the IH-induced decrease in nitrite. Citrulline supplementation significantly decreased myocardial superoxide anion levels and xanthine oxidase enzyme activity under IH. Citrulline shows a cardioprotective capacity by limiting IH-induced pro-oxidant activity. Our results suggest that citrulline might represent a new pharmacological strategy in OSA patients with high cardiovascular risk.

Chronic intermittent hypoxia due to obstructive sleep apnea slightly alters nutritional status: a pre-clinical study

“…cIH had modest effects on nutritional status but with signs of altered protein metabolism. As expected, we observed anorexia, as reported in animal models of cIH (7,8,12). In the same way, previous studies reported an impact of cIH on feeding behavior that is tightly controlled by the central nervous system.…”

“…For this reason, no study yet has tested whether OSAS-induced cIH affects nutritional status, whereas malnutrition during obesity (i.e., sarcopenic obesity) is emerging as a major problem ( 3 – 5 ). First, as previously described, we validated our model by demonstrating that cIH induced an increase in hematocrit ( 12 ). The hypoxia inducible factor-1 (HIF-1)-related erythropoietin (EPO) gene transcription is an adaptative answer to the decrease in PO 2 and is responsible for an increase in hematocrit ( 17 ).…”

“…A preclinical model demonstrated that cIH, which is the major feature of OSAS, is a critical component of glucose homeostasis disturbances, including insulin resistance characterized by decreased insulin sensitivity and increased HOMA-IR (homeostasis 10.3389/fnut.2023.1250529 model assessment of insulin resistance), and dyslipidemia characterized by increased total cholesterol, LDL (low density lipoprotein), or triglyceride levels (6)(7)(8)(9)(10)(11). However, animals exposed to cIH showed decreased food intake, especially along hypoxia exposure, that was associated with a lower body weight (7,8,12), which suggests an alteration of nutritional status.…”

Metformin protects the heart against chronic intermittent hypoxia through AMPK-dependent phosphorylation of HIF-1α

“…OSA is characterized by repetitive pharyngeal collapses leading to chronic intermittent hypoxia (IH). IH is now well recognized to increase infarct size in several rodent models [6][7][8] . In myocardium, IH induces oxidative stress 8,9 and sustained HIF-1 activation 6,7,10 , leading to cardiomyocyte apoptosis through convergent mechanisms such as endoplasmic reticulum (ER) stress 7,11,12 and mitochondrial dysfunction 13,14 .…”

Chronic intermittent hypoxia‐induced cardiovascular and renal dysfunction: from adaptation to maladaptation

“…aorta, mesenteric, pulmonary and ophthalmic arteries) (Arnaud et al., 2018; Friedman et al., 2014; Mentek et al., 2018; Norton et al., 2011; Troncoso Brindeiro et al., 2007). In turn, CIH promotes irreversible oxidative protein modifications (Arnaud et al., 2018; Moya et al., 2016; Ozcan et al., 2022; Siques et al., 2014; Zhou, Wang, et al., 2014) and lipid peroxidation (Castillo‐Galán et al., 2022; Zhou, Wang, et al., 2014). This excessive ROS production can result from a CIH‐induced imbalance between pro‐ and antioxidant systems (Lavie, 2015).…”