Role of NOD1 in Heart Failure Progression via Regulation of Ca2+ Handling.

BACKGROUND: Heart failure (HF) is a complex syndrome associated with a maladaptive innate immune system response that leads to deleterious cardiac remodeling. However, the underlying mechanisms of this syndrome are poorly understood. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a newly recognized innate immune sensor involved in cardiovascular diseases. OBJECTIVES: This study evaluated the role of NOD1 in HF progression. METHODS: NOD1 was examined in human failing myocardium and in a post-myocardial infarction (PMI) HF model evaluated in wild-type (wt-PMI) and Nod1-/- mice (Nod1-/--PMI). RESULTS: The NOD1 pathway was up-regulated in human and murine failing myocardia. Compared with wt-PMI, hearts from Nod1-/--PMI mice had better cardiac function and attenuated structural remodeling. Ameliorated cardiac function in Nod1-/--PMI mice was associated with prevention of Ca2+ dynamic impairment linked to HF, including smaller and longer intracellular Ca2+ concentration transients and a lesser sarcoplasmic reticulum Ca2+ load due to a down-regulation of the sarcoplasmic reticulum Ca2+-adenosine triphosphatase pump and by augmented levels of the Na+/Ca2+ exchanger. Increased diastolic Ca2+ release in wt-PMI cardiomyocytes was related to hyperphosphorylation of ryanodine receptors, which was blunted in Nod1-/--PMI cardiomyocytes. Pharmacological blockade of NOD1 also prevented Ca2+ mishandling in wt-PMI mice. Nod1-/--PMI mice showed significantly fewer ventricular arrhythmias and lower mortality after isoproterenol administration. These effects were associated with lower aberrant systolic Ca2+ release and with a prevention of the hyperphosphorylation of ryanodine receptors under isoproterenol administration in Nod1-/--PMI mice. CONCLUSIONS: NOD1 modulated intracellular Ca2+ mishandling in HF, emerging as a new target for HF therapy.

Functional evaluation of paraplegic monkeys (Macaca mulatta) over fourteen months post-lesion.

We report on the neurological and neurophysiological findings obtained from two adult Macaca mulatta sustaining complete spinal cord transections at T8-T9. We performed periodic neurological exams, recorded motor evoked potentials (MEPs) following transcranial magnetic stimulation (TMS), and recorded electromyograms (EMGs) during the execution of a lower limb motor test. The main observations were: (1) the spinal shock period lasted less than a week; tendon, cutaneous and withdrawal reflexes were uneven in range and occurrence, and Babinski's sign was not observed; (2) a protracted functional lesion in the tibial and common peroneal nerves appeared bilaterally early in the post-lesional period; (3) MEPs were elicited by TMS in the quadriceps muscle of both monkeys; they were recorded as early as the 5th week after lesion in one of the monkeys, and they persisted throughout the post-lesional period in both monkeys; and (4) motor unit action potentials in the quadriceps muscle recorded by EMG were simultaneous with attempts to perform intentional lower limb movements from post-lesion month 11 to 13.5 in both monkeys. The last two sets of observations argue in favor of a partial cortico-spinal functional gain and suggest that spinal cord regeneration can occur after complete spinal cord injury in primates.

Clinical care and evolution of paraplegic monkeys (Macaca mulatta) over fourteen months post-lesion.

We have generated a non-human primate model of complete spinal cord injury (SCI) with a protracted survival time. Two adult Macaca mulatta underwent complete spinal cord transection at T8-T9. We report the effective daily care protocol for over one year survival, the health problems we encountered and the treatments applied. The animals' cages were customized to maintain them in the best possible condition when paraplegic. Daily care, adapted from human care protocols, focused mainly on urinary bladder and skin care, and lower limb rehabilitation. The most important health problems we faced were skin lesions, in particular from self-injury to insensitive regions, and urine voiding dysfunction. Skin lesions were chronic and severe in one of the monkeys. Serious voiding dysfunction occurred temporarily in one monkey in parallel with a high dose oxcarbazepine treatment. The main musculoskeletal complications were vertebral column deformities, which appeared in both monkeys. The rich experience gathered over the lengthy survival period of the two adult paraplegic macaques, the longest to date in the literature, should be useful for other scientists willing to study the long term physiopathological changes that follow SCI as well as the effects of diverse therapeutic strategies before they are applied to humans.

Palmoplantar nonpustular psoriasiform dermatitis in a rhesus macaque.

A case of psoriasiform dermatitis in an adult male rhesus macaque is reported. Appearing spontaneously, the condition presented the clinical and histopathological features of human palmoplantar nonpustular psoriasis. The animal developed multiple scaly plaques on his palms and soles, as well as nail hyperkeratosis and widening of the nail root. Microscopically, the skin lesions showed epidermal hyperkeratosis with multifocal parakeratosis, neutrophil microabscesses in the stratum corneum, a loss of granule cell layer under the microabscesses, acanthosis, and elongation of the rete ridges; the superficial dermis showed a dense inflammatory infiltrate containing lymphocytes, macrophages and neutrophils, as well as dilated and tortuous blood vessels. The lesions improved for 15 days after intramuscular corticosteroid depot therapy and worsened slightly afterwards. Later, a spontaneous, progressive remission coincided with the beginning of spring and lasted until the end of summer; the skin lesions practically disappeared during this period, and the nails looked nearly normal. During the next autumn and winter only nail hyperkeratosis was present. Serum analyses showed hyperproteinaemia and hyperglobulinaemia during the outbreak phase and normal values during remission. The clinical and histopathological features of this case, as well as its evolution, are compared with the three other reported cases of psoriasiform skin lesions in nonhuman primates. To the authors' knowledge, this is the first report of a definite palmoplantar nonpustular psoriasiform dermatitis in a rhesus macaque.