Distinct Effects of Mitochondrial Na+/Ca2+ Exchanger Inhibition and Ca2+ Uniporter Activation on Ca2+ Sparks and Arrhythmogenesis in Diabetic Rats.

Background Mitochondrial dysfunction contributes to the cardiac remodeling triggered by type 2 diabetes (T2D). Mitochondrial Ca2+ concentration ([Ca2+]m) modulates the oxidative state and cytosolic Ca2+ regulation. Thus, we investigated how T2D affects mitochondrial Ca2+ fluxes, the downstream consequences on myocyte function, and the effects of normalizing mitochondrial Ca2+ transport. Methods and Results We compared myocytes/hearts from transgenic rats with late-onset T2D (rats that develop late-onset T2D due to heterozygous expression of human amylin in the pancreatic ß-cells [HIP] model) and their nondiabetic wild-type (WT) littermates. [Ca2+]m was significantly lower in myocytes from diabetic HIP rats compared with WT cells. Ca2+ extrusion through the mitochondrial Na+/Ca2+ exchanger (mitoNCX) was elevated in HIP versus WT myocytes, particularly at moderate and high [Ca2+]m, while mitochondrial Ca2+ uptake was diminished. Mitochondrial Na+ concentration was comparable in WT and HIP rat myocytes and remained remarkably stable while manipulating mitoNCX activity. Lower [Ca2+]m was associated with oxidative stress, increased sarcoplasmic reticulum Ca2+ leak in the form of Ca2+ sparks, and mitochondrial dysfunction in T2D hearts. MitoNCX inhibition with CGP-37157 reduced oxidative stress, Ca2+ spark frequency, and stress-induced arrhythmias in HIP rat hearts while having no significant effect in WT rats. In contrast, activation of the mitochondrial Ca2+ uniporter with SB-202190 enhanced spontaneous sarcoplasmic reticulum Ca2+ release and had no significant effect on arrhythmias in both WT and HIP rat hearts. Conclusions [Ca2+]m is reduced in myocytes from rats with T2D due to a combination of exacerbated mitochondrial Ca2+ extrusion through mitoNCX and impaired mitochondrial Ca2+ uptake. Partial mitoNCX inhibition limits sarcoplasmic reticulum Ca2+ leak and arrhythmias in T2D hearts, whereas mitochondrial Ca2+ uniporter activation does not.

Aß efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas.

Impairment of vascular pathways of cerebral ß-amyloid (Aß) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aß clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aß within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aß co-deposits. LRP1-mediated Aß transport across the blood-brain barrier and Aß clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aß deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aß pathology.

Corrigendum: Intrarenal Renin Angiotensin System Imbalance During Postnatal Life Is Associated With Increased Microvascular Density in the Mature Kidney.

[This corrects the article DOI: 10.3389/fphys.2020.01046.].

Intrarenal Renin Angiotensin System Imbalance During Postnatal Life Is Associated With Increased Microvascular Density in the Mature Kidney.

Environmental stress during early life is an important factor that affects the postnatal renal development. We have previously shown that male rats exposed to maternal separation (MatSep), a model of early life stress, are normotensive but display a sex-specific reduced renal function and exacerbated angiotensin II (AngII)-mediated vascular responses as adults. Since optimal AngII levels during postnatal life are required for normal maturation of the kidney, this study was designed to investigate both short- and long-term effect of MatSep on (1) the renal vascular architecture and function, (2) the intrarenal renin-angiotensin system (RAS) components status, and (3) the genome-wide expression of genes in isolated renal vasculature. Renal tissue and plasma were collected from male rats at different postnatal days (P) for intrarenal RAS components mRNA and protein expression measurements at P2, 6, 10, 14, 21, and 90 and microCT analysis at P21 and 90. Although with similar body weight and renal mass trajectories from P2 to P90, MatSep rats displayed decreased renal filtration capacity at P90, while increased microvascular density at both P21 and P90 (p < 0.05). MatSep increased renal expression of renin, and angiotensin type 1 (AT1) and type 2 (AT2) receptors (p < 0.05), but reduced ACE2 mRNA expression and activity from P2-14 compared to controls. However, intrarenal levels of AngII peptide were reduced (p < 0.05) possible due to the increased degradation to AngIII by aminopeptidase A. In isolated renal vasculature from neonates, Enriched Biological Pathways functional clusters (EBPfc) from genes changed by MatSep reported to modulate extracellular structure organization, inflammation, and pro-angiogenic transcription factors. Our data suggest that male neonates exposed to MatSep could display permanent changes in the renal microvascular architecture in response to intrarenal RAS imbalance in the context of the atypical upregulation of angiogenic factors.

Hypoxia-inducible transcription factors, HIF1A and HIF2A, increase in aging mucosal tissues.

Hypoxia (i.e. oxygen deprivation) activates the hypoxia-signalling pathway, primarily via hypoxia-inducible transcription factors (HIF) for numerous target genes, which mediate angiogenesis, metabolism and coagulation, among other processes to try to replenish tissues with blood and oxygen. Hypoxia signalling dysregulation also commonly occurs during chronic inflammation. We sampled gingival tissues from rhesus monkeys (Macaca mulatta; 3-25 years old) and total RNA was isolated for microarray analysis. HIF1A, HIF1B and HIF2A were significantly different in healthy aged tissues, and both HIF1A and HIF3A were positively correlated with aging. Beyond these transcription factor alterations, analysis of patterns of gene expression involved in hypoxic changes in tissues showed specific increases in metabolic pathway hypoxia-inducible genes, whereas angiogenesis pathway gene changes were more variable in healthy aging tissues across the animals. With periodontitis, aging tissues showed decreases in metabolic gene expression related to carbohydrate/lipid utilization (GBE1, PGAP1, TPI1), energy metabolism and cell cycle regulation (IER3, CCNG2, PER1), with up-regulation of transcription genes and cellular proliferation genes (FOS, EGR1, MET, JMJD6) that are hypoxia-inducible. The potential clinical implications of these results are related to the epidemiological findings of increased susceptibility and expression of periodontitis with aging. More specifically the findings describe that hypoxic stress may exist in aging gingival tissues before documentation of clinical changes of periodontitis and, so, may provide an explanatory molecular risk factor for an elevated capacity of the tissues to express destructive processes in response to changes in the microbial biofilms characteristic of a more pathogenic microbial challenge.

Hippocampal and cognitive aging across the lifespan: a bioenergetic shift precedes and increased cholesterol trafficking parallels memory impairment.

Multiple hippocampal processes and cognitive functions change with aging or Alzheimer's disease, but the potential triggers of these aging cascades are not well understood. Here, we quantified hippocampal expression profiles and behavior across the adult lifespan to identify early aging changes and changes that coincide with subsequent onset of cognitive impairment. Well powered microarray analyses (N = 49 arrays), immunohistochemistry, and Morris spatial maze learning were used to study male F344 rats at five age points. Genes that changed with aging (by ANOVA) were assigned to one of four onset age ranges based on template pattern matching; functional pathways represented by these genes were identified statistically (Gene Ontology). In the earliest onset age range (3-6 months old), upregulation began for genes in lipid/protein catabolic and lysosomal pathways, indicating a shift in metabolic substrates, whereas downregulation began for lipid synthesis, GTP/ATP-dependent signaling, and neural development genes. By 6-9 months of age, upregulation of immune/inflammatory cytokines was pronounced. Cognitive impairment first appeared in the midlife range (9-12 months) and coincided and correlated primarily with midlife upregulation of genes associated with cholesterol trafficking (apolipoprotein E), myelinogenic, and proteolytic/major histocompatibility complex antigen-presenting pathways. Immunolabeling revealed that cholesterol trafficking proteins were substantially increased in astrocytes and that myelination increased with aging. Together, our data suggest a novel sequential model in which an early-adult metabolic shift, favoring lipid/ketone body oxidation, triggers inflammatory degradation of myelin and resultant excess cholesterol that, by midlife, activates cholesterol transport from astrocytes to remyelinating oligodendrocytes. These processes may damage structure and compete with neuronal pathways for bioenergetic resources, thereby impairing cognitive function.