SubSol-HIe is an AMPK-dependent hypoxia-responsive subnucleus of the nucleus tractus solitarius that coordinates the hypoxic ventilatory response and protects against apnoea in mice.

Functional magnetic resonance imaging (fMRI) suggests that the hypoxic ventilatory response is facilitated by the AMP-activated protein kinase (AMPK), not at the carotid bodies, but within a subnucleus (Bregma -7.5 to -7.1 mm) of the nucleus tractus solitarius that exhibits right-sided bilateral asymmetry.

Cardiac function may be compromised in patients with elevated blood cobalt levels secondary to metal-on-metal hip implants.

Aims: Elevated blood cobalt levels secondary to metal-on-metal (MoM) hip arthroplasties are a suggested risk factor for developing cardiovascular complications including cardiomyopathy. Clinical studies assessing patients with MoM hips using left ventricular ejection fraction (LVEF) have found conflicting evidence of cobalt-induced cardiomyopathy. Global longitudinal strain (GLS) is an echocardiography measurement known to be more sensitive than LVEF when diagnosing early cardiomyopathies.

AMPK deficiency in smooth muscles causes persistent pulmonary hypertension of the new-born and premature death.

AMPK has been reported to facilitate hypoxic pulmonary vasoconstriction but, paradoxically, its deficiency precipitates pulmonary hypertension. Here we show that AMPK-α1/α2 deficiency in smooth muscles promotes persistent pulmonary hypertension of the new-born. Accordingly, dual AMPK-α1/α2 deletion in smooth muscles causes premature death of mice after birth, associated with increased muscularisation and remodeling throughout the pulmonary arterial tree, reduced alveolar numbers and alveolar membrane thickening, but with no oedema.

LKB1 is the gatekeeper of carotid body chemosensing and the hypoxic ventilatory response.

The hypoxic ventilatory response (HVR) is critical to breathing and thus oxygen supply to the body and is primarily mediated by the carotid bodies. Here we reveal that carotid body afferent discharge during hypoxia and hypercapnia is determined by the expression of Liver Kinase B1 (LKB1), the principal kinase that activates the AMP-activated protein kinase (AMPK) during metabolic stresses. Conversely, conditional deletion in catecholaminergic cells of AMPK had no effect on carotid body responses to hypoxia or hypercapnia.

AMPK facilitates the hypoxic ventilatory response through non-adrenergic mechanisms at the brainstem.

We recently demonstrated that the hypoxic ventilatory response (HVR) is facilitated by the AMP-activated protein kinase (AMPK) in catecholaminergic neural networks that likely lie downstream of the carotid bodies within the caudal brainstem. Here, we further subcategorise the neurons involved, by cross-comparison of mice in which the genes encoding the AMPK-α1 (Prkaa1) and AMPK-α2 (Prkaa2) catalytic subunits were deleted in catecholaminergic (TH-Cre) or adrenergic (PNMT-Cre) neurons. As expected, the HVR was markedly attenuated in mice with AMPK-α1/α2 deletion in catecholaminergic neurons, but surprisingly was modestly augmented in mice with AMPK-α1/α2 deletion in adrenergic neurons when compared against a variety of controls (TH-Cre, PNMT-Cre, AMPK-α1/α2 floxed).

Cobalt-induced cardiomyopathy - do circulating cobalt levels matter?

Elevated levels of circulating cobalt ions have been linked with a wide range of systemic complications including neurological, endocrine, and cardiovascular symptoms. Case reports of patients with elevated blood cobalt ions have described significant cardiovascular complications including cardiomyopathy. However, correlation between the actual level of circulating cobalt and extent of cardiovascular injury has not previously been performed.

The LKB1-AMPK-α1 signaling pathway triggers hypoxic pulmonary vasoconstriction downstream of mitochondria.

Hypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching in the lungs, is triggered by mechanisms intrinsic to pulmonary arterial smooth muscles. The unique sensitivity of these muscles to hypoxia is conferred by mitochondrial cytochrome c oxidase subunit 4 isoform 2, the inhibition of which has been proposed to trigger HPV through increased generation of mitochondrial reactive oxygen species. Contrary to this model, we have shown that the LKB1-AMPK-α1 signaling pathway is critical to HPV.

AMPK-α1 or AMPK-α2 Deletion in Smooth Muscles Does Not Affect the Hypoxic Ventilatory Response or Systemic Arterial Blood Pressure Regulation During Hypoxia.

The hypoxic ventilatory response (HVR) is markedly attenuated by AMPK-α1 deletion conditional on the expression of Cre-recombinase in tyrosine hydroxylase (TH) expressing cells, precipitating marked increases in apnea frequency and duration. It was concluded that ventilatory dysfunction caused by AMPK deficiency was driven by neurogenic mechanisms. However, TH is transiently expressed in other cell types during development, and it is evident that central respiratory depression can also be triggered by myogenic mechanisms that impact blood supply to the brain.

Myocardial transcriptional profiles in a murine model of sepsis: evidence for the importance of age.

Background: Age influences outcome of sepsis and septic shock. The mechanism of this age-dependent vulnerability to sepsis remains largely unknown. Because much of the mortality and morbidity associated with sepsis and septic shock is the result of severe derangements in the cardiovascular system, it is possible that the myocardium responds to injury in a developmentally influenced manner.