Chemo vs. Mecho

Data strongly suggests interaction between plasma membrane and submembrane at the endothelial surface controls the inflammatory response. 

A meta-analysis from six studies of global gene expression profiles of Blood Pressure (BP) and hypertension was performed in 7017 individuals. 34 genes were differentially expressed. Of these, 6 genes were linked including MYADM, which was the only gene, of 34 discovered across diastolic, systolic BP and hypertension. Knockdown of MYADM (19q13), a component of endothelial surface rafts induced an inflammatory phenotype altering barrier function through the increase of the adhesion receptor ICAM-1 (19p13). This is mediated by MYADM activation of ERM actin cytoskeleton proteins. 

Mechanical forces, without a definitive direction e.g., disturbed flow and relatively undirected stretch at branch points and other complex regions cause sustained molecular signaling of pro-inflammatory and proliferative pathways that include mechanical stretch tied to p53. 

ERM proteins also facilitate Sphingosine-1-phosphate (S1P) dependent egress for T-cells to migrate from lymphoid organs. Their directional migration, by blebbing is contained at the T-cell’s leading edge. This fundamentally different mode of migration is characterized by intracellular pressurization. Of the five S1P receptors S1P2 (19p13) is critical in the immune, nervous, metabolic, cardiovascular, musculoskeletal, and renal systems. Results suggest that the ratio between S1P1 and S1P2 (19p13) governs the migratory behavior of different T cell subsets. 

Human NK cells express S1P1 mRNA. Activation with IL-2 increases S1P1, promotes S1P4 (19p13) and S1P5 (19p13) but not S1P2 (19p13) expression. Unlike S1P1, S1P2 (19p13) signals through several different G-alpha subunits, Gi, G12/13, and Gq. S1P5 (19p13) is also expressed in human and mouse NK cells and was required for mobilization to inflamed organs. S1P5-deficient mice had aberrant NK cell homing during steady-state conditions. NK cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. 

Virus-infected mast cells selectively recruit NK cells and positively modulate their functions through mechanisms dependent on soluble mediators, such as interferons. Skin mast cells protect mice against vaccinia virus by triggering mast cell receptor S1P2 (19p13) and releasing antimicrobial peptides. S1P2 (19p13),  a negative regulator of platelet derived growth factor (PDGF) induced migration and proliferation as well as SphK1 expression. 

S1P inhibits macropinocytosis (internalizing extracellular materials) and phosphorylation of Akt via S1P2 (19p13) stimulation resulting in diminished antigen capture.

S1P1, S1P2 (19p13) and S1P3 receptors have redundant or cooperative functions for the development of a stable and mature vascular system during embryonic development. S1P2 (19p13)  and S1P3 are involved in regulation of endothelial barrier function, fibrosis, and vasoconstriction. 

Adipogenic differentiation is inhibited by S1P2 (19p13) as mediated by C/EBPα and PPARγ, which induces PEPCK, a more recent gene of interest in cancer that acts at the junction between glycolysis and the Krebs cycle.

Mecho or chemo, chicken or egg, what first?

Systolic Blood Pressure and Innate Immunity vs. the Cancer Brain

Participants with a valid heart disease phenotype (atherosclerosis) were identified in a MESA blood pressure analysis conducted over 10 years. The valid group varied from 770 to 1113 patients from whom further blood analysis queried a primary and exploratory hypothesis of immune cell subsets. Four statistically significant innate cell subsets were discovered to be associated with Systolic blood pressure (SBP); Natural Killer (NK) cells, gamma delta T cells and classical monocytes.

Separately, an analysis of 7017 individuals from 6 international studies of gene expression signatures for SBP, diastolic blood pressure (DBP) and hypertension (HTN) found 7717 genes of which 34 were most differentialy expressed. Enrichment analysis for the systolic and diastolic gene group's associated to NK cell mediated cytotoxicity and 13 other pathways including antigen processing and inflammatory response, pointing strongly to innate and adaptive immunity. MYADM was the only gene identified for all groups SBP, DBP and HTN.

MYADM controls endothelial barrier function through ezrin, radixin, and moesin (ERM)-dependent regulation of ICAM-1 expression. ERM expression is required for ICAM-1 expression in response to MYADM suppression or TNF-α. ICAM-1 is a paradigmatic adhesion receptor that regulates leukocyte adhesion together with integrin LFA-1. This connection between endothelial membrane and cortical actin cytoskeleton appears to modulate the inflammatory response at the blood tissue barrier. 

Pressure overload activates the sympathetic nervous system (SNS) and up-regulates p53 expression in the cardiac endothelium and in bone marrow (BM) cells. Increased p53 expression promotes endothelial-leukocyte cell adhesion and initiates inflammation in cardiac tissue, which exacerbates systolic dysfunction. SNS activates, at least by significant increase of circulating norepinephrine (NE), which up-regulates p53 expressions, while forced expression of p53 increased ICAM-1 expression. 

On endothelial cells SNS is mediated via catecholamine-β2-adrenergic signaling, which up-regulates the production of reactive oxygen species (ROS), activates p53 and induces cellular senescence. Immune cells, including macrophages, monocytes, NK cells, B and T cells express the β2-adrenergic receptor and catecholamine. During pressure overload, NE cultured macrophages up-regulated p53 expression, whereas introduction of p53 increased Itgal (LFA-1) expression (which binds ICAM-1). Treatment with NE increased ROS, which was attenuated after inhibition of β2- adrenergic signaling in macrophages. Endothelial cell–macrophage interaction via NE-ROS-p53 signaling induces up-regulation of adhesion molecules, thus contributing to cardiac inflammation and systolic dysfunction.

During hypertension the vascular endothelium activates monocytes, in part through ROS by a loss of nitric oxide (NO) signaling, increased release of IL-6, hydrogen peroxide and a parallel increase in STAT activation in adjacent monocytes. NO inhibits formation of intermediate monocytes and STAT3 activation. Humans with hypertension have increased intermediate and non-classical monocytes and  intermediate monocytes demonstrate evidence of STAT3 activation. Mice with experimental hypertension exhibit increased aortic and renal infiltration of monocytes, dendritic cells, and macrophages with activated STAT3.

A senescence-associated secretory phenotype (SASP) was induced in epithelial cells after DNA damage of sufficient magnitude. In premalignant epithelial cells SASPs induced an epithelial–mesenchyme transition and invasiveness, hallmarks of malignancy by a paracrine mechanism that largely depended interleukin (IL)-6 and IL-8. Strikingly, loss of p53 and gain of oncogenic RAS exacerbated the pro-malignant activities. This suggests a cell-non-autonomous mechanism by which p53 can restrain and oncogenic RAS can promote the development of age-related cancer by altering the tissue microenvironment. Oncogenic signaling pathways inhibit the p53 gene transcription rate through a mechanism involving Stat3, which binds to the p53 promoter in vitro and in vivo. Blocking Stat3 in cancer cells up-regulates expression of p53, leading to p53-mediated tumor cell apoptosis. 

Induced stretch or stretch from pressure overload may engage a non-autonomous, p53 centric micro-mechanical mechanism that escalates or deescalates innate responses against cells functioning outside the mechanical ranges that macrophages or NK cells permit. Thus, the neuro-immune extension through SNS signaling, may begin with circulating blood pressure or stretch promoted through inflammation. 

Not Only A Killer A System for Killing!

The next time you're out exercising, spare a thought for your busy mitochondria. NASA scientists just reported mitochondria as the key to health problems in space.

Natural killer (NK) cells can extend membrane probes into cells or pathogens. These are loaded with granulysin (GNLY) to penetrate and perforin (PFN) to kill intracellular bacteria or protozoa and can lyse entire cells. The probes can also transfer healthy mitochondria to apoptotic cardiomyocytes (and other cells) in need of mitochondrial transfer. Uterine NK cells of the decidua send probes into trophoblasts to selectively kill intracellular Listeria monocytogenes without killing the trophoblast host. Stressed cells, moving toward apoptosis can behave similarly, but in reverse shooting out nanoprobes to proximal cells seeking cooperation and urgent mitochondrial transfers including to cancer cells.

A meta-analysis of gene expression signatures for blood pressure and hypertension in 7017 individuals from 6 international studies found of 7717 genes, 34 were most differentialy expressed including GNLY. Enrichment analysis for the diastolic and systolic gene group's associated strongly with NK cell mediated cytotoxicity and 13 other pathways including antigen processing and inflammatory response.

Formation of membrane probes or tubes, in which mitochondria travel and establishment of intracellular mitochondrial networks in the peripheral zone of cells require Kinesin-1 heavy chain (KIF5B). KIF5B is also required for female meiosis (oogenesis) and proper chromosomal segregation in mitotic cells and modulates central spindle organization in late-stage cytokinesis in chondrocytes.

A study of centromere heterochromatin (connected with central spindle) surprisingly showed that distant euchromatic regions, enriched in repressed methylated genes also interacted with the hierarchical organization of centromeric DNA. These 3D spatial interactions (at a distance) are likely mediated by liquid-like fusion events and can influence the health of individuals. Repressed gene's were identified as transposable elements, sequences often associated with pathogenic DNA insertions that have been persistently retained.  

KIF5B is an interaction partner of ADP-ribosylation factor-like 8b (Arl8b), which is required for NK cell–mediated cytotoxicity that drives polarization of lytic granules and microtubule-organizing centers (MTOCs) toward the immune synapse between NK and target cells. Silencing experiments that led to failure of MTOC-lytic granule polarization suggest Arl8b and KIF5B together control the critical step in NK cell cytotoxicity. 

KIF5B is also a critical transporter of p53 and c-Myc to the cytoplasm for degradation. However, subcellular localization of Arl8b and p53-dependent cell death was shown to occur through knockdown of acetylation subunit NatC. As a consequence, p53 is stabilized, phosphorylated and significantly activates transcription of downstream proapoptotic genes. In the absence KIF5B, or presence of  mutants p53 and c-Myc aggregate in the nucleus where they signal DNA damage-induced apoptosis through the control of p53 by endogenous c-Myc (in vivo).

Finely tuned, frequently used KIF5B in NK cells expressing GNLY may induce effects on local tissue blood pressure, as was discovered by expression of Renin-Angiotensin vasoactive proteins AT1, AT2, and ANP in pregnancy-induced uterine NK cells. Inflammation signaling, via tissue bound NK cells may result from stretch-mediated release of angiotensin II, which is coupled with p53 acetylation apoptosis and activation of p53. This may prolong upregulation of the local renin-angiotensin system, increase susceptibility of target cells to apoptosis and signal adaptive immune cells. 

Somewhere in the balance between NatC knockdown induced apoptosis and angiotensin II induced apoptosis p53 may direct traffic to keep your cells healthy!

 

p53 vasoregulation and NK cell depletion in SARS-CoV2

p53 has earned first prize in the academic stakes. It is also the most mutated gene in cancer and elephant's have 20 copies, which probably explains their surprisingly low rate of cancer. Its associations to innate immunity, particularly Natural Killer (NK) cells through the mechanics of vasoconstriction-dilation have become a point of interest in COVID19 patients.

Remarkably COVID19 has inspired the global scientific community to focus a significant portion of its aggregate research toward the impact of  SARS-CoV2 (CoV2). For the first time in history global research is singularly focused because a large number of other protein's and gene's are affected by CoV2 binding Ace2. The Ace2 receptor is important in systems of vasoconstriction-dilation and has wide ranging impact.

CoV2 binding Ace2 reduces its availability to convert Angiotensin1 to Angiotensin 1-7 (Ang1-7) or Angiotensin 1-9 (Ang1-9), which primarily interact via MAS and Angiotensin2 Receptor (AT2R) respectively. These have been linked to signaling and stretch caused by vasoconstriction-dilation, mitochondrial dysfunction, mitochondrial fission as well as cardiac and vascular remodeling.

Ang1-7 and Ang1-9 interactions with MAS or AT2R cell surface receptors have been linked to signaling events that drive p53 binding DNA and transcription. Myocyte stretching activates p53 and p53-dependent genes, leading to the formation of Angiotensin II (Ang II) and apoptosis. AngII, stimulates phosphorylation of p53 (on serine 15) and CREB (on serine 133) and signaling converges on the p53-CRE enhancer to stimulate Bradykinin receptor 2 (BK2) gene transcription. BK2 is a key element in the p53 related kallikrein-kinin system (KKS) of vasodilation that counters the Renin-Angiotensin-Aldosterone-System (RAAS) of vasoconstriction. 

Aldosterone was shown to induce mitochondrial dysfunction and podocyte injury mediated by p53/Drp1-dependent mitochondrial fission. In neuronal cells p53 dependent declines in Drp1 and parkin contribute to altered mitochondrial morphology and cell death. Parkin, via Pink1 activity binds depolarized mitochondria to induce autophagy of mitochondria. Mutations in both Drp1 and Pink1 were fatal in Drosophila models. These events also implicate a direct functional link to chronic inflammation in ageing between p53 and expression levels of ICAM1 on endothelial and NK cells required to bind targets. The p53 mediated negative regulation of autophagy is Pink1 dependent and experiments have shown that mitochondrial antigens, recognized by NK cells presented on MHC's are Pink1 and parkin dependent. 

Severe COVID-19 patients have highly elevated Bradykinin and AngII, perhaps an indication of elevated p53 trends that have been discovered in these patients. Under normal circumstances, on endothelial cells Bradykinin would act as a potent vasodilator via its BK2 receptor. However, since Ang (1-7) potentiates Bradykinin action on BK2 receptors its near absence may reduce KKS vasodilation. On the other hand RAAS, also via p53 and elevated AngII primarily interacts with AT1R to promote vasoconstriction.  

NK cells through their Renin Angiotensin System may counter-regulate target cells in response. However, in COVID19 patients depletion of NK cells, invasion of Neutrophils and endothelial cell damage, in part through elevated p53 autophagy and apoptosis is the overwhelming nasty work of CoV2 against the backdrop of dysregulated blood pressure in tissue.

 

 

p53 in the SARS-CoV2 Storm

Coronavrius induced cytokine storm

A massive simulation and analysis using the supercomputer at Oakridge led scientists to more accurately identify the general idea that a Covid19 induced "cytokine storm" is responsible for disease progression. After detailed genetic analysis they specifically predicted that Bradykinin (BK) initiated the storm. If correct, this would help improve treatment directions for admitted patients. 

BK receptors are coded by BDKRB1 and BDKRB2 (BK2) gene's that operate in a kallikrein-kinin system (KKS), like the Renin Angiotensin System (RAS) as another potent regulator of blood pressure. BK is a part of the vasopressor system that induces hypotension and vasodilation, it is degraded by ACE and enhanced by angiotensin1-9, which is produced by ACE2 the receptor that SARS-COV2 binds. BK has been implicated as being active in the metabolic response to stress.

Similar to angiotensin peptides, BK is produced from an inactive pre-protein kininogen through activation by serine protease kallikrein (KKL). KLK1-KLK15 are mostly represented as a cluster of serine proteases on chromosome 19, with different tissue distributions. 

KLK's 1-15 further evidence a convergence on chromosome 19, associated closely with a large number of genes involved in blood pressure. KLK's are located at 19q13.41, an active transposon region with a 2x background deletion rate clustered near Zinc Fingers and KIR's (Killer cell like receptors). Chr19 is also associated with MHC precursors around which innate immunity and Natural Killer (NK) cell signaling developed. A link was confirmed in mice uterine NK cells that regulated local tissue blood pressure by at least Angiotensin Type 1 Receptor (AT1R) partly in response to mechanical stretch of vasoconstriction and vasodilation induced by uterine NK's internal RAS. 

A study of BK2 confirmed a conserved p53 binding site (rat, mouse and human) and p53-mediated activation of the BK2 promoter was augmented by transcriptional co-activators, CBP/p300. The results demonstrated BK2 promoter as a target of the p53-mediated activation and suggested a new physiological role for p53 in the regulation of G protein-coupled receptor (GPCR) gene expression. 

A follow up study, by the same group explained that Angiotensin II (AngII), the product of Angiotensin-Renin-Angiotensin1-Ace stimulates the phosphorylation of p53 (on serine 15) and CREB (on serine 133), and that AngII signaling converges on the p53-CRE enhancer to stimulate BK2 gene transcription.  

The convergence revealed that AT1R signaling activated CREB phosphorylation and in vivo assembly of p-CREB on the BK2 promoter in conjunction with histone hyperacetylation. It confirmed that AngII stimulates BK2 gene transcription in IMCD3 cells via AT1R. Thus, under conditions of augmented AngII and AT1R signaling, BK expression will be enhanced, thereby maintaining a balance of these two powerful counter-regulatory systems representing a novel form of cross-talk between GPCR's that link RAS and KKS, crucially here via p53.

This combined research indicates that activation of BK2 on endothelial cells, which is mediated by p53 dependent RAS-KKS cross-talk may also implicate AT1R on NK cells to secrete growth disrupting or growth promoting factors in response. SARS-CoV2 bound to ACE2 reduces its availability to convert angiotensin 1 to angiotensin 1-9, which normally enhances BK. The resulting imbalance and increase in circulating angII may directly implicate a NK cells' AT1R RAS response to a CoV2-ACE2 bound cell with disabled p53 promoter of GPCR expression. This cell with a crippled BK2 KKS, hypotension-vasodilation response offers no counter to the the AngII induced NK RAS vasoconstrictive function, affecting local tissue blood pressure thus failing to become a NK target. 

Blood Pressure by Natural Killer Cells and SARS-CoV2

A meta-analysis of gene expression signatures for diastolic, systolic blood pressure and hypertension found that out of 7717 unique, related genes 34 were most differentialy expressed across 7017 individuals from 6 international studies. No less than 20% of the 34 gene's, were located on Chromosome 19. Enrichment analysis for the diastolic and systolic gene group's associated to Natural Killer (NK) Cell mediated cytotoxicity and 13 other pathways including antigen processing and inflammatory response, pointing strongly to innate and adaptive immunity. 

I covered the NK origin of MHC and antigen immunity and reproduction at Chromosome 19 on a previous blog, now the meta-analysis adds infection, immunity and blood pressure to this location. Evolutionary detectives tracked events from Chromosome 19 to 1,6 and 9 via transposon re-combination events, which provided further direction for interpreting the blood pressure meta-analysis. A review of the genes and pathways involved increasingly characterized innate immunity as an integrated core component of almost every aspect of our skeletal, circulatory, tissue and neuronal systems. 

Blood pressure is enormously complex, but its governance of entropy under the mechanical laws of molecular diffusion and disassociation reign supreme. Renin-Angiotensin (RAS) genes are widely recognized to be the cornerstones needed for blood pressure. Innate immune cells including NK have been confirmed to possess and express RAS genes. Macrophages, a member of innate immune system have been linked to angiotensin signaling neuropathic pain as well as bacterial infection inducing pain suppression by angiotensin 2 receptor (AT2R).  Maternal NK cells AT1R and AT2R have been implicated in the control of localized blood pressure in placental tissues leading to preeclampsia a condition in pregnancy.

In various studies, including in disease conditions it has been shown and suggested that different male:female ratios between AT1R and AT2R in monocytes and other innate cells is an important factor in the determination of blood pressure that has been extensively studied in heart and lung conditions. AT2R plays a critical role in satellite cell differentiation and skeletal muscle regeneration via myoblasts, which may be the reason it's expressed ubiquitously in developing fetal tissue. It's likely that balance between AT1R and AT2R signaling is critical for normal muscle regeneration.  

In addition to the role of NK cells in blood pressure a study using lung-intravital microscopy linked pulmonary NK cells to the control of neutrophil intravascular motility, response to acute inflammation and diminished pathogenic accumulation. NK cell derived IFN-γ plays an important role in the activation and maturation of monocytes into macrophages and dendritic cells, an amplifying mechanism in the early innate inflammatory response. Angiotensin II can induce rapid neutrophil infiltration via AT1R that also stimulates leucocyte–endothelium interactions. Inhibited IFN-γ signaling ameliorated Angiotensin II induced cardiac damage, which led to a finding that NK-cells play an essential role in the induced vascular dysfunction.

Ace2 Expression Patterns in Covid19

Pathophysiology of Covid19 demonstrates that NK cells are depleted and neutrophils infiltrate into lung tissue leading to tissue damage and escalation of the disease. By SARS-CoV2 binding the Ace2 receptor of vascular epithelial and other cells, the conversion of Angiotensin II is blocked (image above), therefore upregulated. Increased levels of Angiotensin II were shown to induce NK cells to release IFN-γ. On recruitment to inflammatory sites, NK-cells release IFN-γ and engage with monocytes in a reciprocal program of activation in which monocytes mature into macrophages and dendritic cells. NK exhaustion results and is a known outcome that may relate to IFN-γ levels. However, in patients with high expression of Ace2, NK cell counts are lower and cytokine expressions do not show up during the initial disease state pointing to the role of accumulating Angiotensin II.  

Covid19 Meta Analysis

The image above shows distribution of expression (y axis) for ACE2, PCSKs (blood pressure mediation) and TMPRSS2 (CoV2 S1 cleavage) across lung cell types (x axis). It completes the picture that Corin-Furin mediated control over blood pressure normalization is a significant component of Covid19 disease progression and NK cells are a central player.

Molecules targeting RAS are a major focus of inhibitory or complementary therapeutic design, but a modified NK cell that is shielded from SARS-CoV2 may be the tool-in-the-shed our immune systems need. 

Does SARS-CoV2 Strangle P53 to kill Natural Killer Immunity?

Codondex iScore

It's intriguing to speculate why p53 regulates the cardiac transcriptome and the ATIP gene, at least to transcribe ATIP1 a human isoform of the Angiotensin II AT2 Receptor Interacting Protein? The gene's different names describe its various functions including; Mitochondrial tumor suppressor 1 (MTSG1) or Microtubule-Associated Scaffold Protein 1 (MTUS1). Expression of MTUS1 was reported lost in various types of human malignancies such as colon, ovarian, head-and-neck, pancreas, breast cancers, bladder, gastric, and lung cancers.

AT2 is a receptor associated with Renin-Angiotensin System (RAS) and vasodilation that confers potential benefits in pathogenic conditions. It is not highly expressed on Natural Killer (NK) cells, but has been detected and was shown in a rat model of myocardial infarction to reduce injury and have dampening effects on inflammation. The AT2 receptor, in combination with ATIP1 is also reported as a tumor suppressor. New experimental evidence showed interaction defects between ATIP1 and two mutant forms of the AT2 receptor identified in cases of mental retardation. The studies point to a functional role of the AT2-ATIP1 axis in cognition.

p53 is a major transcription factor and the TP53 gene is the most mutated in cancer. It has been the extended subject of this blog and our research into relationships between p53 and Natural Killer cells. Our interest is p53 genetic signatures used to select specific diseased cells to co-culture and educate NK cells that can be applied as custom, target therapy against various diseases.

As reported in a previous blog entry, RAS is a cornerstone of blood pressure which has been directly implicated in Coronavirus patients whose NK cells have also been severely depleted. Transcriptomic analyses identified several immune pathways and pro-inflammatory cytokines induced by SARS-CoV-2 infection evidencing a sustained inflammation and cytokine storm. Pathway analysis revealed that patient’s lymphopenia may be caused by activation of apoptosis and p53 signaling pathway in lymphocytes.

If, as reported the RAS of NK cells contributes to the control of blood pressure via the localized ratio of AT1:AT2 expression. Then, in the capillaries of tissue micro-environments the delicate balance of vasoconstriction<>vasodilation signaling may be exploited by NK cells scanning the affected cells to deliver their innate inflammatory response. Cytokine directed vascular changes that effect local blood pressure may be another varied contributor.

So, with these time-bound, localized, micro-pressure effects in progress how does an innate NK cell go about killing an infected target that may have also motivated its AT1:AT2 response? AT2 was found to be an AT1 antagonist, which adds complexity to the function and ratio effects of this diverse protein. ATIP is an agonistic factor of AT2 to exert opposing effects to AT1, such as organ-protective and anti-inflammatory effects. We know ATIP's including ATIP1 binds AT2's cytoplasmic tail and impacts signaling that results from Angiotensin II (AngII) binding AT2's extracellular domain. We also know p53 transcribes at least ATIP1 and that ATIP3 is directly implicated in microtubule organization.

ATIP1 has been previously reported to localize either at the mitochondria or the Golgi. These apparently discordant results might be reconciled if ATIP1 were a microtubule-associated protein. Indeed, mitochondrial organelles are highly enriched on microtubules that ensure their intracellular transport. On the other hand, the Golgi apparatus is located at the nuclear periphery close to the microtubule organizing center (MTOC). ATIP1 might thus associate with microtubules and provide a direct link between the AT2 receptor at the cell membrane and the cytoskeleton.

The prospect that RAS related signaling and p53 are tied in both lymphocytes and broader cell biology is tantalizing. Among the cellular signaling pathways, p53 plays a prominent role in RAS. Activation of p53 increases Angiotensin and AT1 expression. Conversely, AngII activates p53 pathway to mediate its downstream cellular effects. Mechanically, stretch-mediated release of AngII induces myocyte apoptosis by activating p53 that enhances the local renin-angiotensin system and decreases the Bcl-2-to-Bax protein ratio in the cell. 

In Cardiometabolic Disease pathogen-associated, molecular pattern–mediated metabolic reprogramming can be considered a manifestation of innate immune signal reprogramming a conserved phenomenon that changes how we think about the biology and function of the innate immune network including indispensable acetylation that destabilizes p53 and its inhibitor MDM2.

In Coronavirus patients, SARS-CoV2 binding ACE2 receptors may modify processes associated with the ACE2/Ang-(1-7)/Mas axis and acute, chronic inflammation, including reported leukocyte influx. The mechanical stretch of vasoconstriction<>vasodilation could cause AngII to activate p53. Therefore, if SARS-CoV2 impedes the AngII-ACE2-AT2-ATIP1 pathway that under normal circumstances in NK cells may direct microtubules to form an immune synapse for target killing, then the rapidly multiplying virus binding ACE2 may simultaneously render NK ineffective and by mechanical-stretch affect cardiomyocytes by p53 activation, which would lower AT2 ratios, including in vascular epithelial cells to induce apoptosis or G2/M cell death. A potent cocktail indeed!

SARS-CoV2, Blood Pressure and Natural Killer Cells

The Cardiac Cycle

A beating heart is the first sign of life in the developing fetus. Cells of the heart's ventricular and aortic cavities express various proteins with non-active natriuretic and diuretic peptides in a pattern associated with blood pressure. Activated Corin or Furin proteins cleave these peptides into shorter active forms. The cleavage site often defines how these peptides influence cells and the cellular processes while circulating in blood. But, the heart is not the only place this mix of proteins and peptides are manufactured. From early to late pregnancy Corin level changes were greater in women who developed gestational hypertension, commensurate with diastolic and mean arterial blood pressure and it got doctors and scientists thinking?

NT-proBNP is a pro-hormone, a Corin or Furin dependent peptide from the same molecule as activated BNP. Both are released when pressure changes inside the heart. Circulating levels of NT-proBNP were higher in early and late-onset preeclampsia. BNP mRNA and protein were also detected in placentas from women with preeclampsia and controls. In normal pregnancies, BNP in plasma is stable, but in severe preeclampsia it is elevated. In 181 preeclampsia patients higher levels of Corin were expressed, also secreted from synctiotrophoblasts and extravillous trophoblasts of the placenta.

The secretion of NT-proBNP, and BNP mRNA and receptors were investigated in cultured primary trophoblasts. Low levels of NT-proBNP were found in the supernatants of term, but not first-trimester trophoblasts. In preeclampsia patients Corin mRNA and protein in uterine tissue were significantly lower, but plasma Corin higher, compared to normal pregnancies. These apparently conflicting reports may relate to local blood pressure.

A paper studying Atrial Natriuretic Peptide (ANP) identified that Corin and ANP promoted trophoblast invasion and spiral artery remodeling in the developing placenta. Pregnant Corin or ANP-deficient mice developed high blood pressure and proteinuria, characteristics of preeclampsia. Further, trophoblast invasion and uterine spiral artery remodeling were markedly impaired. Consistently ANP potently stimulated human trophoblasts invading in Matrigels. That Corin is up-regulated with stromal cell decidualization and strongly localized provides compelling evidence to support localized, but not circulating Corin activating ANP within these uterine cells. This may then invite trophoblast and Natural Killer (NK) cell invasion and the ultimate handshake of fetal trophoblasts with maternal endothelial cells lining spiral arteries of the developing placenta.

In early pregnancy NK cells expand to become the largest population of immune cells in decidua lining the uterus (uNK). They are closely associated with the development of blood vessels including spiral artery remodeling and possess a functional Renin- Angiotensin system, cornerstones of blood pressure. ANP antagonizes Angiotensin II receptor type 1 (AT1) leading to vasoconstriction. The ratio of uNK cells expressing AT1 markedly changed between gestation day 6 and 10. At day 10-12 ANP strongly co-localized to uNK cells at implantation sites, immediately after spiral arterial modification. Expression of vasoregulatory molecules by uNK cells suggests they contribute to the changes in blood pressure that occur between days 5 and 12 coincidental with their expansion during normal pregnancy in mice.

Studies of patients with Pulmonary Arterial Hypertension have also implicated BNP in the decline of NK cells and CD8+ T-Cells. A similar depletion was recently reported in Coronavirus  patients and expression of NT-proBNP was significantly elevated.  It is reasonable to infer that blood pressure and NK cells are associated especially in the tight confines of pulmonary capillaries or placental tissue.  Perhaps its their capacity to express molecules that participate in Corin activated vasoregulation through natriuretic peptides and to be immunoreactive, or perhaps their reaction to kill infected cells results from it - who knows?

In addition to the well documented natriuresis, diuresis and vasodilation, BNP may also modulate immune and inflammatory reaction to cardiac injury. BNP depletes monocytes, B lymphocytes and NK cells in peripheral blood. BNP regulates the chemotaxis of monocytes and production of inflammatory molecules by macrophages. BNP may promote cardiac neutrophil infiltration and also have direct effects on matrix remodeling and wound healing. All of these characteristics have been observed in lungs of critical care and deceased Coronavirus patients.