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Genomics and Inflammation in Cardiovascular Disease

Isha S. Dhande, Peter A. Doris

10.1002/cphy.c200032

Source: Volume 11, Issue 4, October 2021

Published online: September 2021

Full Article on Wiley Online Library



Abstract

Chronic cardiovascular diseases are associated with inflammatory responses within the blood vessels and end organs. The origin of this inflammation has not been certain, and neither is its relationship to disease clear. There is a need to determine whether this association is causal or coincidental to the processes leading to cardiovascular disease. These processes are themselves complex: many cardiovascular diseases arise in conjunction with the presence of sustained elevation of blood pressure. Inflammatory processes have been linked to hypertension, and causality has been suggested. Evidence of causality poses the difficult challenge of linking the integrated and multifaceted biology of blood pressure regulation with vascular function and complex elements of immune system function. These include both, innate and adaptive immunity, as well as interactions between the host immune system and the omnipresent microorganisms that are encountered in the environment and that colonize and exist in commensal relationship with the host. Progress has been made in this task and has drawn on experimental approaches in animals, much of which have focused on hypertension occurring with prolonged infusion of angiotensin II. These laboratory studies are complemented by studies that seek to inform disease mechanism by examining the genomic basis of heritable disease susceptibility in human populations. In this realm too, evidence has emerged that implicates genetic variation affecting immunity in disease pathogenesis. In this article, we survey the genetic and genomic evidence linking high blood pressure and its end‐organ injuries to immune system function and examine evidence that genomic factors can influence disease risk. © 2021 American Physiological Society. Compr Physiol 11:2433‐2454, 2021.

Figure 1. Figure 1. The innate and adaptive immune system. Illustration of the components of the immune system which is broadly divided into the “innate” and “adaptive” arms. Innate immunity provides immediate but nonspecific responses against pathogens, whereas the adaptive immune system provides a delayed but more specific response to antigens and is characterized by a long‐term “memory” to recognize prior‐antigen exposures. DCs, dendritic cells; Macs, macrophages; NK cells, natural killer cells; NKT cells, natural killer T cells; γδT cells, gamma delta T cells.
Figure 2. Figure 2. Angiotensin II (AII) and immune signaling pathways. Illustration of the proposed signaling pathways by which AII can modulate immune function. Ang II, angiotensin II; AP‐1, activator protein‐1; AT1R, angiotensin type I receptor; ATF‐2, activated transcription factor‐2; DAG, diacylglycerol; ER, endoplasmic reticulum; ERK 1/2, extracellular signal‐regulated kinase 1/2; IP3, inositol 1,4,5‐trisphosphate; JAK, Janus kinase; JNK, c‐Jun N‐terminal kinase; MEK 1/2, mitogen‐activated/ERK kinase 1/2; NADPH, nicotinamide adenine dinucleotide‐reduced; NFAT, nuclear factor of activated T cells; NF‐κB, nuclear factor kappa‐light‐chain enhancer of activated B cells; PKC, protein kinase C; PLC, phospholipase C; ROS, reactive oxygen species; SP‐1, specific protein‐1; STATs, signal transducers and activators of transcriptions.
Figure 3. Figure 3. V(D)J recombination in lymphocyte development. Illustration of the mechanism of V(D)J recombination that is essential for the creation of T‐ and B‐cell receptors. Recombination‐activating genes 1 and 2 (encoded by RAG1 and RAG2) and DNA‐dependent protein kinase (DNA‐PK, encoded by PRKDC) shown in red are key enzymes that facilitate recombination and lymphocyte maturation.
Figure 4. Figure 4. Effect of angiotensin II (AII) infusion on blood pressure (BP) in Rag1−/− mice. Conflicting reports from studies examining the pressor effects of AII (490 ng/kg/min) in Rag1−/− mice, with Guzik et al. demonstrating that lack of T and B cells rendered mice resistant to AII‐hypertension, while Seniuk et al. report that there was no difference in pressor response to AII in Rag1−/− mice and wild‐type C57BL6 controls. Bottom: Reused, with permission, from Seniuk A, et al., 2020 99, © 2020, Wolters Kluwer. Top: Reused, with permission, from Guzik TJ, et al., 2007 38, © 2007, Rockfeller University Press.
Figure 5. Figure 5. Zinc finger nuclease (ZNF) technology to create knockout rats. Illustration of the application of ZFN to introduce double‐stranded nicks at precise regions in DNA in fertilized embryos to create targeted gene‐deleted rats. NHEJ: non‐homologous end joining.
Figure 6. Figure 6. Servo control of renal perfusion pressure (RPP). Illustration of the functional components of a servo‐control setup for maintaining baseline renal perfusion pressure in the left kidney, while allowing the right kidney to be exposed to the pressor effects of AII infusion in rats. The upper panel was taken from: Pavlov TS, Levchenko V, O'Connor PM, Ilatovskaya DV, Palygin O, Mori T, Mattson DL, Sorokin A, Lombard JH, Cowley AW Jr, Staruschenko A. Deficiency of renal cortical EGF increases ENaC activity and contributes to salt‐sensitive hypertension. J Am Soc Nephrol. 2013 Jun;24(7): 1053‐62. DOI: 10.1681/ASN.2012080839. Epub 2013 Apr 18. PMID: 23599382; PMCID: PMC3699826. The lower panel was from: Mori T, Cowley AW Jr. Role of pressure in angiotensin II‐induced renal injury: chronic servo‐control of renal perfusion pressure in rats. Hypertension. 2004 Apr;43(4): 752‐9. DOI: 10.1161/01.HYP.0000120971.49659.6a. Epub 2004 Feb 23. PMID: 14981064.
Figure 7. Figure 7. Effect of high salt on immune signaling. Illustration of the effects of high sodium concentration, via ENaC activation, on downstream signaling cascades in T cells and macrophages. Activation of p38 by high salt results in p38 MAPK activation, leading to serum glucocorticoid kinase 1 (SGK1) and nuclear factor of activated T cells 5 (NFAT5) in both T cells and macrophages, leading to activation of specific transcription profiles. High salt is associated with a pathogenic TH17 phenotype and skews macrophages to a pro‐inflammatory M1 phenotype.
Figure 8. Figure 8. Risk alleles for autoimmune disease. A Manhattan plot illustrating the genome‐wide distribution of risk alleles for autoimmune disease with variants on the X‐axis plotted against statistical strength of association (−Log10P) on the Y‐axis. This genetic risk is distributed largely among genes involved in T‐ and B‐cell interactions, and a cluster of variants can influence disease risk for multiple pathological conditions involving immune function. Petersone L, Edner NM, Ovcinnikovs V, Heuts F, Ross EM, Ntavli E, Wang CJ, Walker LSK. T cell/B cell collaboration and autoimmunity:An intimate relationship. Front Immunol 9: 1941, 2018. DOI: 10.3389/fimmu.2018.01941.
Figure 9. Figure 9. PTPN22/PTPN2 in immune signaling pathways. Illustration of the T‐cell receptor (TCR)‐mediated signaling pathways negatively regulated by the protein tyrosine phosphatase nonreceptor type 22 and 2 (PTPN22/PTPN2). Allelic variants, notably the R620W allele, result in gain‐of‐function phenotypes that predispose to autoimmune disease.


Figure 1. The innate and adaptive immune system. Illustration of the components of the immune system which is broadly divided into the “innate” and “adaptive” arms. Innate immunity provides immediate but nonspecific responses against pathogens, whereas the adaptive immune system provides a delayed but more specific response to antigens and is characterized by a long‐term “memory” to recognize prior‐antigen exposures. DCs, dendritic cells; Macs, macrophages; NK cells, natural killer cells; NKT cells, natural killer T cells; γδT cells, gamma delta T cells.


Figure 2. Angiotensin II (AII) and immune signaling pathways. Illustration of the proposed signaling pathways by which AII can modulate immune function. Ang II, angiotensin II; AP‐1, activator protein‐1; AT1R, angiotensin type I receptor; ATF‐2, activated transcription factor‐2; DAG, diacylglycerol; ER, endoplasmic reticulum; ERK 1/2, extracellular signal‐regulated kinase 1/2; IP3, inositol 1,4,5‐trisphosphate; JAK, Janus kinase; JNK, c‐Jun N‐terminal kinase; MEK 1/2, mitogen‐activated/ERK kinase 1/2; NADPH, nicotinamide adenine dinucleotide‐reduced; NFAT, nuclear factor of activated T cells; NF‐κB, nuclear factor kappa‐light‐chain enhancer of activated B cells; PKC, protein kinase C; PLC, phospholipase C; ROS, reactive oxygen species; SP‐1, specific protein‐1; STATs, signal transducers and activators of transcriptions.


Figure 3. V(D)J recombination in lymphocyte development. Illustration of the mechanism of V(D)J recombination that is essential for the creation of T‐ and B‐cell receptors. Recombination‐activating genes 1 and 2 (encoded by RAG1 and RAG2) and DNA‐dependent protein kinase (DNA‐PK, encoded by PRKDC) shown in red are key enzymes that facilitate recombination and lymphocyte maturation.


Figure 4. Effect of angiotensin II (AII) infusion on blood pressure (BP) in Rag1−/− mice. Conflicting reports from studies examining the pressor effects of AII (490 ng/kg/min) in Rag1−/− mice, with Guzik et al. demonstrating that lack of T and B cells rendered mice resistant to AII‐hypertension, while Seniuk et al. report that there was no difference in pressor response to AII in Rag1−/− mice and wild‐type C57BL6 controls. Bottom: Reused, with permission, from Seniuk A, et al., 2020 99, © 2020, Wolters Kluwer. Top: Reused, with permission, from Guzik TJ, et al., 2007 38, © 2007, Rockfeller University Press.


Figure 5. Zinc finger nuclease (ZNF) technology to create knockout rats. Illustration of the application of ZFN to introduce double‐stranded nicks at precise regions in DNA in fertilized embryos to create targeted gene‐deleted rats. NHEJ: non‐homologous end joining.


Figure 6. Servo control of renal perfusion pressure (RPP). Illustration of the functional components of a servo‐control setup for maintaining baseline renal perfusion pressure in the left kidney, while allowing the right kidney to be exposed to the pressor effects of AII infusion in rats. The upper panel was taken from: Pavlov TS, Levchenko V, O'Connor PM, Ilatovskaya DV, Palygin O, Mori T, Mattson DL, Sorokin A, Lombard JH, Cowley AW Jr, Staruschenko A. Deficiency of renal cortical EGF increases ENaC activity and contributes to salt‐sensitive hypertension. J Am Soc Nephrol. 2013 Jun;24(7): 1053‐62. DOI: 10.1681/ASN.2012080839. Epub 2013 Apr 18. PMID: 23599382; PMCID: PMC3699826. The lower panel was from: Mori T, Cowley AW Jr. Role of pressure in angiotensin II‐induced renal injury: chronic servo‐control of renal perfusion pressure in rats. Hypertension. 2004 Apr;43(4): 752‐9. DOI: 10.1161/01.HYP.0000120971.49659.6a. Epub 2004 Feb 23. PMID: 14981064.


Figure 7. Effect of high salt on immune signaling. Illustration of the effects of high sodium concentration, via ENaC activation, on downstream signaling cascades in T cells and macrophages. Activation of p38 by high salt results in p38 MAPK activation, leading to serum glucocorticoid kinase 1 (SGK1) and nuclear factor of activated T cells 5 (NFAT5) in both T cells and macrophages, leading to activation of specific transcription profiles. High salt is associated with a pathogenic TH17 phenotype and skews macrophages to a pro‐inflammatory M1 phenotype.


Figure 8. Risk alleles for autoimmune disease. A Manhattan plot illustrating the genome‐wide distribution of risk alleles for autoimmune disease with variants on the X‐axis plotted against statistical strength of association (−Log10P) on the Y‐axis. This genetic risk is distributed largely among genes involved in T‐ and B‐cell interactions, and a cluster of variants can influence disease risk for multiple pathological conditions involving immune function. Petersone L, Edner NM, Ovcinnikovs V, Heuts F, Ross EM, Ntavli E, Wang CJ, Walker LSK. T cell/B cell collaboration and autoimmunity:An intimate relationship. Front Immunol 9: 1941, 2018. DOI: 10.3389/fimmu.2018.01941.


Figure 9. PTPN22/PTPN2 in immune signaling pathways. Illustration of the T‐cell receptor (TCR)‐mediated signaling pathways negatively regulated by the protein tyrosine phosphatase nonreceptor type 22 and 2 (PTPN22/PTPN2). Allelic variants, notably the R620W allele, result in gain‐of‐function phenotypes that predispose to autoimmune disease.
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Article Title: Genomics and Inflammation in Cardiovascular Disease
 

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Isha S. Dhande, Peter A. Doris. Genomics and Inflammation in Cardiovascular Disease. Compr Physiol 2021, 11: 2433-2454. doi: 10.1002/cphy.c200032