PubMed · 13015668
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1952. VERATRUM.. https://pubmed.ncbi.nlm.nih.gov/13015668/
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The pathogenic mechanism underlying diseases caused by mitochondrial DNA (mtDNA) mutation, including hypertension, persists as an unresolved global challenge. Although mutation-induced mitochondrial defects have been well characterized, how these mito-perturbations are converted into critical intermediary signaling cascades and contribute to diseases remain unknown. Here, using human induced pluripotent stem cell (hiPSC)-derived vascular organoids (VOs) and vascular cells, the hypertensive mt. tRNAIle4263A > G mutation was identified to induce vascular senescence, apoptosis and vascular-specific dysfunction through mitochondria-endoplasmic reticulum (ER) interaction. For the first time, this study mapped the transcriptional reprogramming landscape of human VOs carrying this mutation. Through systematic screening and functional validation, ER stress was screened out, together with downstream mitochondria-associated ER membranes-mitochondrial Ca2+ overload resulting in vascular abnormality. Pathological reactive oxygen species (ROS) elevation, driven by tRNAIle destabilization and bioenergetic failure, acts as the primary instigator of maladaptive ER stress activation in this cascade. Pharmacological targeting of this axis-using mito-Tempol (a mitochondria-targeted ROS scavenger), Tauro Ursodeoxycholic Acid (an ER stress inhibitor), or RU265 (a highly-selective mitochondrial calcium uniporter inhibitor)-rescues vascular abnormality. This study highlights mt. tRNAIle4263A > G mutation orchestrates vascular pathology through ROS induced activation of inter-organelle communication, resolving a long-standing knowledge gap between mtDNA mutations and diseases and establishing therapeutic nexuses for mtDNA mutation-related cardiovascular diseases.
BACKGROUND: T cells are critical in the pathogenesis of hypertension. IL (interleukin)-16 is primarily produced and secreted by T cells; however, its role in hypertension remains unclear. METHODS: Serum samples from patients with hypertension were collected and analyzed using ELISA. A mouse model of Ang II (angiotensin II)-induced hypertension was established, and the role of IL-16 was investigated. RESULTS: IL-16 expression was elevated in patients with hypertension and positively correlated with both systolic and diastolic blood pressure. In Ang II-induced hypertensive mice, IL-16 expression was significantly upregulated in serum, kidney, and aortic tissues. IL-16-neutralizing antibody reduced both systolic and diastolic blood pressure in response to Ang II. Histological analyses revealed that renal injury and vascular remodeling were attenuated after IL-16 neutralization. Mechanistically, T-cell-derived IL-16 enhanced CD4+ (cluster of differentiation 4) T helper 1 cell function and mediated crosstalk with macrophages to stimulate inflammatory responses via activation of NF-κB (nuclear factor kappa B) and MAPK (mitogen-activated protein kinase) pathways. Conditioned medium from macrophages primed with IL-16-treated T helper 1 cells promoted smooth muscle cell proliferation and exacerbated endothelial cell damage during hypertension progression. CONCLUSIONS: Collectively, these findings indicate that T-cell-derived IL-16 exacerbates Ang II-induced hypertension and associated organ damage by promoting a T helper 1-macrophage-driven proinflammatory response.
Two members of a recently discovered family of protein kinases {WNK1 and WNK4 [with no K (lysine) kinases-1 and -4]} are the cause of an inherited disease known as pseudohypoaldosteronism type II that features arterial hypertension. The family is known as WNK due to a lack of the invariant catalytic lysine in kinase subdomain II. The mechanisms by which WNKs regulate blood pressure are beginning to be understood at the physiological level from recent studies showing effects of WNK4 on several plasma membrane co-transporters and ion channels. However, little is known about the function of WNKs at the biochemical level. In this issue of the Biochemical Journal, Vitari et al. have shown that WNK1 and WNK4 interact with other kinases, SPAK (STE20/SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress response kinase-1), which are involved in the regulation of ion transporters. WNK1 and WNK4 phosphorylate SPAK and OSR1, which in turn phosphorylate the N-terminal domain of the basolateral Na+-K+-2Cl- co-transporter, NKCCl. The phosphorylation site involved in SPAK or OSR1 activation is identified as a threonine residue within the T-loop.