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Abstract

  1. Top of page
  2. Abstract
  3. Myocardial Redox Stress and Remodeling in CMS
  4. Metabolic Hepatopathy: NAFLD/NASH
  5. Intimal Redox Stress and ECM Remodeling in Vasculature
  6. Pancreatic Islet Redox Stress, Islet Amyloid, and ECM Remodeling
  7. Neural Redox Stress and Remodeling
  8. Endothelial Redox Stress and Remodeling
  9. Renal Redox Stress and Remodeling
  10. Conclusion
  11. References

The cardiometabolic syndrome is a construct associated with an increased risk of type 2 diabetes mellitus, cardiovascular disease (coronary artery disease , peripheral arterial disease, and stroke), chronic kidney disease, and the metabolic hepatopathy referred to as nonalcoholic fatty liver disease or nonalcoholic steatohepatitis. Thus , the term cardiometabolic syndrome includes all of these metabolic, islet, cardiovascular, renal, and hepatic disorders and clustering clinical syndromes. This overview of the cardiometabolic syndrome is designed to review the clinical complications and the end-organ cellular and extracellular matrix remodeling events that occur with the cardiometabolic syndrome. The MINER acronym will serve as an outline, representing: Myocardial and metabolic—hepatopathy, Intimal and islet, Neurovascular, Endothelial, and Renal oxidation—reduction (redox) stress and remodeling.

The cardiometabolic syndrome (CMS) is characterized by an array of metabolic, hemodynamic, islet, hepatic, neurovascular, cardiovascular (CV), and renal abnormalities coupled with multiple metabolic risk factor toxicities, all associated with increased formation of reactive oxygen species (ROS) (Figure 1). The A-FLIGHT-U acronym summarizing these factors is set forth in Table I.1 The driving force behind CMS is obesity (specifically, visceral obesity). Insulin resistance (IR) and the compensatory endocrine β-cell—derived hyperinsulinemia, hyperproinsulinemia, and hyperamylinemia contribute to many of the components of the CMS and seem to be central and unifying factors.1

image

Figure 1. Organ involvement in the cardiometabolic syndrome (CMS), a complex clinical clustering with multiple metabolic risk factors. The four arms of the background X represent the four major components of the CMS: hyperinsulinemia (hyperproinsulinemia, hyperamylinemia), hypertension, hyperlipidemia—obesity, and hyperglycemia (impaired glucose tolerance [IGT] and impaired fasting glucose). Central to this syndrome are insulin resistance (IR) and the production of reactive oxygen species (ROS). T2DM=type 2 diabetes mellitus; pCOS=polycystic ovary syndrome; CKD=chronic kidney disease; NAFLD=nonalcoholic fatty liver disease; NASH=nonalcoholic steatohepatitis; CVD=cardiovascular disease; pAI=plasminogen activator inhibitor; XO=xanthine oxidase; hsCRP=high-sensitivity C-reactive protein; FFA=free fatty acids; eNOS=endothelial NO synthase; RAAS=renin-angiotensin-aldosterone system; Ang II=angiotensin II

Table I.  The A-FLIGHT-U Acronym: Multiple Injurious Stimuli Responsible for the Production of Reactive Oxygen Species (ROS)
AAngiotensin II activation of NAD(P)H oxidase toxicity [RIGHTWARDS ARROW] ROS
 Amylin (hyperamylinemia) islet amyloid polypeptide toxicity
 Advanced glycosylation/fructosylation end products
 Aging
 Antioxidant reserve compromised; absence of antioxidant network
 Asymmetric dimethyl arginine
 Adipose/adipocytokine toxicity
 Albuminuria, microalbuminuria
FFree fatty acid toxicity
LLipids-leptin toxicity
IInsulin toxicity (endogenous hyperinsulinemia-hyperproinsulinemia)
 Inflammation toxicity
GGlucotoxicity
HHypertension/homocysteine/high sensitivity C-reactive protein toxicity
TTriglyceride toxicity
UUric acid-xanthine oxidase toxicity
 Uncoupling functional eNOS-structural endothelial tissue
NAD(P)H=nicotinamide adenine dinucleotide phosphate reduced; [RIGHTWARDS ARROW]=leading to; eNOS=endothelial NO synthase

Other clinical conditions associated with this syndrome are essential hypertension, abnormalities in the circadian rhythm of blood pressure and heart rate, the diabetic dyslipidemic syndrome, hypercoagulability, hyperuricemia, increased CV inflammation, endothelial dysfunction, and microalbuminuria, all of which contribute to an increased risk of developing type 2 diabetes mellitus (T2DM), CV disease (CVD), chronic kidney disease (CKD), and nonalcoholic fatty liver disease (NAFLD), with increased morbidity and mortality. This article reviews current knowledge about the dynamic interrelationship of the various factors that make up the CMS and its implications for individuals with and without T2DM.

The acronym MINER (Myocardial and metabolic—hepatopathy, Intimal and islet, Neurovascular, Endothelial, and Renal oxidation—reduction [redox] stress and remodeling) will serve as an outline for this overview regarding the cellular and extracellular matrix (ECM) remodeling associated with each of the involved end-organs (Table II).2

Table II.  The MINER Acronym: End-Organ Complications
 End-Organ ComplicationsCollagen Types
MMyocardial remodelingI–III, IV
 Mixed basement membrane (BM) and interstitial remodeling 
 Diastolic dysfunction 
 Diabetic cardiomyopathy 
 Systolic dysfunction 
 Overt congestive heart failure 
 Metabolic hepatopathyI–III, IV
 Nonalcoholic fatty liver disease 
 Nonalcoholic steatohepatitis 
IIntimal remodelingI–III, IV
 Mixed BM and interstitial remodeling 
 Accelerated diabetic atherosclerosis [RIGHTWARDS ARROW] atheroscleropathy 
 Diffuse cardiovascular disease 
 Islet remodelingI–III, IV
 Mixed BM and interstitial disease; islet fibrosis 
 Progressive decline in insulin secretion and absorption 
NNeurovascular remodelingI–III, IV
 Mixed BM and interstitial remodeling 
 Primarily symmetric peripheral sensorimotor 
EEndothelium and capillary BM remodelingIV
 Primarily a BM disease 
 Endothelial dysfunction with endothelial NO synthase uncoupling and decreased endothelial NO 
 Pericyte dysfunction/disease: capillary remodelingI, III
 Perivascular/pericapillary fibrosis affecting the blood-brain, blood-nerve, and blood capillary-BM barriers 
 Functional: endothelial NO synthase uncoupling 
 Structural: endothelial-tissue uncoupling with pericapillary fibrosis 
RRenal remodeling: glomerular and interstitialI–III, IV
 Mixed BM and interstitial disease 
 Primarily a BM disease with interstitial fibrosis 
 Microalbuminuria [RIGHTWARDS ARROW] macroalbuminuria [RIGHTWARDS ARROW] progressive end-stage renal disease and failure 
Reactive oxygen species, oxidation-reduction stress, and remodeling are associated with each of the target organs. Each target organ will represent a combination of vascular and interstitial remodeling: initially, there is a structural change which will evolve into a functional change and the associated diabetic complications. [RIGHTWARDS ARROW]=leading to

Myocardial Redox Stress and Remodeling in CMS

  1. Top of page
  2. Abstract
  3. Myocardial Redox Stress and Remodeling in CMS
  4. Metabolic Hepatopathy: NAFLD/NASH
  5. Intimal Redox Stress and ECM Remodeling in Vasculature
  6. Pancreatic Islet Redox Stress, Islet Amyloid, and ECM Remodeling
  7. Neural Redox Stress and Remodeling
  8. Endothelial Redox Stress and Remodeling
  9. Renal Redox Stress and Remodeling
  10. Conclusion
  11. References

Diastolic dysfunction relates to an excessive and stiffened ECM associated with cellular myocyte remodeling hypertrophy, which results in a thickened myocardial wall and impaired ventricular relaxation. This is in contrast to systolic dysfunction, which is associated predominately with an impaired ejection fraction. Diastolic dysfunction is an abnormality seen early in the CMS, and this abnormality is associated with reduced insulin responsiveness and increased oxidative stress.3,4 Congestive heart failure may develop acutely following a myocardial infarction/recurrent ischemic events or insidiously over time in association with the CMS (Figure 2).5

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Figure 2. Putative mechanisms for myocardial remodeling in the cardiometabolic syndrome (CMS). Interstitial extracellular matrix (ECM) consisting of types I and III collagen and elastin with fibrosis is indicated by blue. Matrix metalloproteinases and activation of oxidation—reduction stress act upon endomysial struts and ECM leading to myocardial remodeling. Hyperinsulinemia, hyperamylinemia, and hyperproinsulinemia activate a local tissue renin-angiotensin-aldosterone system (RAAS) and local reactive oxygen species (ROS) production through nicotinamide adenine dinucleotide phosphate reduced (NAD[P]H) oxidase. Advanced glycation end products (AGEs) which are indicated by red colorization overlying blue might also contribute to diastolic dysfunction. Pericapillary fibrosis (PCF) has also been implicated in myocardial dysfunction as well as other end-organs affected by CMS. Myofibroblasts (MyoFB) represented in green contribute to excessive ECM and fibrotic changes within the myocardium. Ang II=angiotensin II; TGF=transforming growth factor; AT=angiotensin receptor type

Multiple metabolic toxicities (A-FLIGHT-U) play a role in the development of ROS and cardiac disease in the CMS (Table I).5 In addition to accelerated ischemic and hypertensive cardiomyopathy, there exists a specific metabolic cardiomyopathy with minimal epicardial disease that is characterized by early diastolic dysfunction progressing to systolic dysfunction and eventual congestive heart failure.6–8 Additional abnormalities of the heart associated with the CMS are reviewed by Peterson and colleagues in this issue of the Journal of the CardioMetabolic Syndrome (JCMS ).

Metabolic Hepatopathy: NAFLD/NASH

  1. Top of page
  2. Abstract
  3. Myocardial Redox Stress and Remodeling in CMS
  4. Metabolic Hepatopathy: NAFLD/NASH
  5. Intimal Redox Stress and ECM Remodeling in Vasculature
  6. Pancreatic Islet Redox Stress, Islet Amyloid, and ECM Remodeling
  7. Neural Redox Stress and Remodeling
  8. Endothelial Redox Stress and Remodeling
  9. Renal Redox Stress and Remodeling
  10. Conclusion
  11. References

NAFLD represents a spectrum of fatty liver disorders with remodeling changes ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cryptogenic cirrhosis, and end-stage liver disease (Figure 3).9 NASH is the most prevalent form of progressive liver disease in the United States, approaching 5% (currently thought to exceed that of hepatitis cirrhosis).10,11 NAFLD and NASH may be considered the hepatic component of the CMS and are strongly associated with CMS, obesity, and T2DM (Table II). Many authors have proposed that NASH be included as a clinical feature of the CMS and IR.12–14

image

Figure 3. Metabolic hepatopathy in the cardiometabolic syndrome. Hematoxylin and eosin micrographs of liver in nonalcoholic fatty liver disease. A) Simple fatty liver; steatosis without inflammation or fibrosis; B) nonalcoholic steatohepatitis; C) fibrosis—cirrhosis (cryptogenic cirrhosis).

The initial cellular remodeling consists of the intracellular hepatocyte accumulation of fat due to increased lipolysis and excessive generation of triglycerides and free fatty acids. This intracellular accumulation of fat is associated with enhanced oxidative stress and generation of ROS within the hepatocytes, while setting in motion a panoply of metabolic and intracellular and extracellular remodeling events within the liver.

The hepatic stellate cell (a sinusoidal pericyte cell) is central to the underlying ECM accumulation and fibrosis. As a pericyte cell, it initially begins laying down ECM (types I and III collagen) adjacent to the hepatic sinusoids and may be responsible for a sinusoidal—endothelial cell hepatic parenchyma uncoupling both functionally and structurally. Over time, the stellate cells are responsible for the extensive remodeling within the liver, contributing to end-stage liver failure, which may necessitate liver transplantation (Figure 4). This process is discussed in detail by Ibdah and colleagues in this issue of JCMS.

image

Figure 4. Pericapillary—perisinusoidal fibrosis and edema in the cardiometabolic syndrome; 14-week-old Zucker obese model demonstrating pericapillary or perisinusoidal fibrosis and edema in the liver. Within the sinusoid is a pair of Kuppfer cells (KC). Note the loss of microvilli and the loss of the space of Disse. Sinusoid pericyte hepatic stellate cell (HSC) is important for synthesizing the excess perisinusoidal extracellular matrix, resulting in fibrosis. EC=endothelial cell

Intimal Redox Stress and ECM Remodeling in Vasculature

  1. Top of page
  2. Abstract
  3. Myocardial Redox Stress and Remodeling in CMS
  4. Metabolic Hepatopathy: NAFLD/NASH
  5. Intimal Redox Stress and ECM Remodeling in Vasculature
  6. Pancreatic Islet Redox Stress, Islet Amyloid, and ECM Remodeling
  7. Neural Redox Stress and Remodeling
  8. Endothelial Redox Stress and Remodeling
  9. Renal Redox Stress and Remodeling
  10. Conclusion
  11. References

In CMS there is both microvessel disease within the intima (adventitia-derived vasa vasorum) and macrovessel disease (accelerated atherosclerosis) located at the same sites of vulnerable atherosclerotic plaques within the arterial vessel wall (Figure 5).15 This angiogenic intimal pathology is very similar to diabetic retinopathy and plays an important role in destabilizing vulnerable atherosclerotic plaques via intimal intraplaque hemorrhage. Neovascularization is the most powerful independent predictor of plaque rupture (p=0.001), followed by disruption of the internal elastic lamina (p=0.01) and fibrous cap thinness (p=0.02).16

image

Figure 5. Atherothrombosis in the cardiometabolic syndrome. A) Vulnerable plaque rupture; B) vulnerable plaque erosion; C) complicated multi-layering plaque; D) malignant-like angiogenesis—neovascularization of the media and intima reminiscent of the neovascularization found in diabetic retinopathy

Atherogenesis occurs in the intima and contains fibrillar macromolecules such as collagens, proteoglycans (PGs), hyaluronan, and extracellular glycans and PGs within the intima and result in the accumulation of atherogenic lipoproteins.18

Atherosclerotic lesions in CMS constantly undergo remodeling and may assume multiple types of different multidomain proteins. The negatively charged glycosaminoglycans attached to PGs are responsible for the retention of lipoproteins in early atherogenesis.17 CMS and the A-FLIGHT-U toxicities are believed to alter these glycosaminoplaques, as outlined in the American Heart Association's classification (types I—VIII).19 There are at least two major types of plaque morphology in sudden death and acute coronary syndromes: plaque rupture and plaque erosion (Figure 5). Plaque rupture is associated with a large lipid core, a thin fibrous cap, macrophage inflammatory changes at the shoulder, decreased vascular smooth muscle cells in the fibrous cap, and plaque vasa vasorum angiogenesis, while plaque erosion is associated with endothelial denudation and formation of thrombosis without rupture of the plaque and is accompanied by an increase in vascular smooth muscle cells and subendothelial PG matrix accumulation. Another common lesion in CMS is the complicated lesion with multi-layering of the atherosclerotic lesion and luminal stenosis (Figure 5).

Differential regulation of the PGs versican and hyaluronan (with its CD44 integrin) in the subendothelial—intima space in plaque erosion, promoting increased vascular smooth muscle cells and increased synthesis of PGs (specifically hyaluronan and CD44), may interfere with the endothelial cell's adhering to its basement membrane (BM). In addition, hyaluronan and CD44 have been shown to mediate the adhesion of platelets to hyaluronan, which could accelerate thrombus formation.20 Further, calcification proteins (thrombospondin-1 and matrix gamma carboxyglutamic acid protein) within the ECM predispose to plaque remodeling. A fundamental abnormality in this process is an increased redox signaling system via ROS, which recruits vascular inflammatory cells, culminating in cellular and ECM remodeling.21

Pancreatic Islet Redox Stress, Islet Amyloid, and ECM Remodeling

  1. Top of page
  2. Abstract
  3. Myocardial Redox Stress and Remodeling in CMS
  4. Metabolic Hepatopathy: NAFLD/NASH
  5. Intimal Redox Stress and ECM Remodeling in Vasculature
  6. Pancreatic Islet Redox Stress, Islet Amyloid, and ECM Remodeling
  7. Neural Redox Stress and Remodeling
  8. Endothelial Redox Stress and Remodeling
  9. Renal Redox Stress and Remodeling
  10. Conclusion
  11. References

Compensatory hyperinsulinemia, hyperproinsulinemia, and hyperamylinemia associated with IR and the loss of normal hormonal homeostasis by the islet β cell are associated with the activation of a local-tissue islet renin-angiotensin-aldosterone system (RAAS). Islet RAAS activation and increased tissue angiotensin II (Ang II) are associated with increased ECM fibrosis and disordered islet architecture, oxidative—redox stress, and β-cell apoptosis. Islet remodeling in CMS is related to ROS and multiple metabolic toxicities (A-FLIGHT-U).22,23 The ECM remodeling in the islet is strikingly similar to those changes found in the myocardium, with the major difference being the presence of islet amyloid.

In rodent models of the CMS, ECM fibrosis develops and is associated with a delay in first-phase insulin secretion. This process is ameliorated with RAAS blockade utilizing angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.23 Islet fibrosis could serve as a barrier to nutrient/toxic metabolic products, which contributes to the development of a barrier to insulin diffusion from the β cell to the systemic microcirculation; however, this has yet to be investigated. Findings of improved functional islet response associated with the structural improvement in ECM fibrosis remodeling are believed to be important and may help to explain the delay in the development of overt T2DM with RAAS blockade in recent clinical trials.23 In a 14-week-old Zucker obese model of the CMS, we have recently made preliminary observations of a transitional stage demonstrating the early changes of BM thickening in islet tissue and early development of pericapillary fibrosis (Figure 6).

image

Figure 6. Basement membrane (BM) thickening and pericapillary fibrosis in the 14-week-old Zucker obese model of the cardiometabolic syndrome. A) BM transitional remodeling with alternating thick and thin segments. B) Pericapillary fibrosis similar to the perisinusoidal fibrosis in the liver in Figure 4. The pericapillary fibrosis represents an endothelial capillary—organ tissue uncoupling, which may result in impaired trafficking of nutrient supply to the cellular tissue and also impaired trafficking of tissue endocrine and paracrine production (such as hormones and cytokines), as well as impaired uptake of the noxious byproducts of cellular metabolism.

Amylin (islet amyloid polypeptide)-derived islet amyloid deposition occurs in humans and nonhuman primates because they have an amyloidogenic form of amylin, whereas other species do not have amyloidogenic amylin, due to a different amino acid sequence of their native β-cell—derived amylin. , At autopsy, up to 90% of patients with T2DM demonstrate amylin-derived islet amyloid, which may contribute to its progressive nature and may be considered a conformational disease.2

Oligomers of amylin are known to be toxic to islet (3 cells, resulting in apoptosis. A recent publication revealed the exciting finding that rosiglitazone (a peroxisome proliferator-activated receptor y agonist) protects human islet cells against apoptosis from human islet amyloid polypeptide by a phosphatidylinositol 3'-kinase Akt-dependent pathway2 In CMS, there is an accelerated free radical polymerization of amylin-derived oligomers into the large islet amyloid polypeptide aggregates, which create a space-occupying lesion within the islet. These lesions may be responsible for a diffusion barrier, secretory, and absorptive defect directed against endogenous insulin diffusion and absorption by islet capillaries. Islet remodeling (Figure 7) associated with islet amyloid deposition is most often associated with islet fibrosis, adipose accumulation, and intimal remodeling.27 Various aspects of pancreatic islet abnormalities in CMS are discussed more extensively by Drs. Lastra and Manrique in this issue of JCMS.

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Figure 7. Islet amyloid remodeling associated with insulin resistance, reactive oxygen species, and hyperamylinemia in the cardiometabolic syndrome. A) Hematoxylin and eosin micrograph of a single islet with areas of islet amyloid; B) an artistic rendition of the islet in a three-dimensional view. The image also portrays the blue β cells centrally and the yellow α cells and pinkish β cells peripherally.

Neural Redox Stress and Remodeling

  1. Top of page
  2. Abstract
  3. Myocardial Redox Stress and Remodeling in CMS
  4. Metabolic Hepatopathy: NAFLD/NASH
  5. Intimal Redox Stress and ECM Remodeling in Vasculature
  6. Pancreatic Islet Redox Stress, Islet Amyloid, and ECM Remodeling
  7. Neural Redox Stress and Remodeling
  8. Endothelial Redox Stress and Remodeling
  9. Renal Redox Stress and Remodeling
  10. Conclusion
  11. References

The symmetric distal sensorimotor polyneuropathy, diabetic polyneuropathy, may be associated with impaired glucose tolerance of the CMS.28 Many of the neurovascular (vasa nervorum) and ECM remodeling changes of the neuronal unit remodeling of diabetic polyneuropathy may be associated with the multiple metabolic toxicities associated with the CMS and the increased propensity for stroke associated with the CMS.29

Endothelial Redox Stress and Remodeling

  1. Top of page
  2. Abstract
  3. Myocardial Redox Stress and Remodeling in CMS
  4. Metabolic Hepatopathy: NAFLD/NASH
  5. Intimal Redox Stress and ECM Remodeling in Vasculature
  6. Pancreatic Islet Redox Stress, Islet Amyloid, and ECM Remodeling
  7. Neural Redox Stress and Remodeling
  8. Endothelial Redox Stress and Remodeling
  9. Renal Redox Stress and Remodeling
  10. Conclusion
  11. References

The endothelium, with its BM, is the first line of defense against injurious stimuli, due to its unique interfacing position between the vessel wall and circulating blood. It is responsible for the regulation of vascular tone, circulation, fluidity, coagulation and vascular inflammatory responses, oxidative stress, and remodeling in response to injurious stimuli. BM remodeling with thickening and leakiness has been previously reviewed and discussed in earlier sections on intimal and islet redox stress and remodeling.2

Endothelial perturbations and dysfunction are central to each of the CMS complications of the MINER acronym. Endotheliopathy represents the endothelial dysfunction found in the CMS and is frequently present for many years before the diagnosis of end-organ complications. Increased vascular generation of ROS, under the auspices of increased Ang II-mediated nicotinamide adenine dinucleotide phosphate (reduced) oxidase activity, results in increased destruction of generated endothelial NO (eNO).30 There are at least four major sources for vascular ROS production associated with oxidative—redox stress in CMS: 1) membraneous nicotinamide adenine dinucleotide phosphate (reduced) oxidase (Ang II driven); 2) xanthine oxidase; 3) mitochondrial electron leak due to excess energy supply from glucose and free fatty acids; and 4) uncoupling of the endothelial NO synthase (eNOS) enzyme. ROS also result in tetrahydrobiopterin oxidation to trihydrobiopterin and bihydrobiopterin.31 This causes tetrahydrobiopterin, eNOS5 and L-arginine uncoupling, reducing eNOS production of eNO. Instead of the endothelium being a net producer of protective eNO, it becomes a net producer of the deleterious potent oxidant superoxide and exacerbates redox stress by allowing ROS to beget ROS (Figure 8).

image

Figure 8. Endothelial NO (eNO) synthase (eNOS) uncoupling in the cardiometabolic syndrome. Uncoupling of the essential tetrahydrobiopterin (BH4 ) cofactor to L-arginine results in increased production of reactive oxygen species. If BH4 is oxidized then oxygen will react with the nicotinamide adenine dinucleotide phosphate reduced (NAD[P]H) oxidase enzyme to become a net producer of superoxide ([O2—]). FAD=flavin adenonucleotide; FMN=flavin mononucleotide; OX=oxidation; Haem=hemoglobin; NADP+=nicotinamide adenine dinucleotide phosphate; ADMA=asymmetric dimethylarginine; BH2=dihydrobiopterin; BH3=trihydrobiopterin

Endogenous Inhibitor of the eNOS Enzyme: Asymmetric Dimethylarginine. ROS, hyperlipidemia, hyperhomocysteinemia, glucotoxicity, and renal hemodialysis all facilitate asymmetric dimethylarginine production. Asymmetric dimethylarginine inhibits eNOS by competing with native substrate L-arginine and reduces the production of protective eNO.32,33

eNOS Gene Polymorphism. In addition to superoxide, the eNOS enzyme itself may be dysfunctional, due to a mutation of the 1203-amino acid eNOS enzyme protein. At least one important gene polymorphism has been identified in humans.34,35 The Glu298[RIGHTWARDS ARROW]Asp (G894T polymorphism) is associated with an increased risk of hypertension, nephropathy, hyperhomocysteinemia, accelerated atherosclerosis, increased incidence of recurrent CV events, and the development of impaired glucose tolerance and T2DM. This suggests a new genetic susceptibility factor for hyperinsulinemia, IR, and T2DM.34

In summary, the healthy endothelium is a net producer of eNO, which is impaired in the CMS when superoxide generation is increased. Furthermore, increased tissue Ang II, hyperglycemia, and dyslipidemia are capable of interacting with one another, as well as with environmental stressors such as smoking, overnutrition, and underexercise, to uncouple the eNOS reaction.

Renal Redox Stress and Remodeling

  1. Top of page
  2. Abstract
  3. Myocardial Redox Stress and Remodeling in CMS
  4. Metabolic Hepatopathy: NAFLD/NASH
  5. Intimal Redox Stress and ECM Remodeling in Vasculature
  6. Pancreatic Islet Redox Stress, Islet Amyloid, and ECM Remodeling
  7. Neural Redox Stress and Remodeling
  8. Endothelial Redox Stress and Remodeling
  9. Renal Redox Stress and Remodeling
  10. Conclusion
  11. References

The CMS predisposes to an increased risk not only of CVD, T2DM, and stroke but also CKD and renal redox stress and remodeling.36,37 Diabetic nephropathy is the leading cause of end-stage renal failure and renal replacement therapy.

Histopathologic changes consist of glomerular, renovascular, and tubulointerstitial ECM remodeling. The basic lesion is a pronounced thickening of the BM of glomerular capillaries, arterioles, and collecting tubules, and tubulointerstitial fibrosis. In addition, there are changes of inflammation, with monocyte-derived macrophages as well as mesangial cell hyperplasia and marked mesangial matrix expansion within the glomeruli (Figure 9).

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Figure 9. Renal oxidation—reduction stress and remodeling in the cardiometabolic syndrome. Left: Normal renal capillary glomerular and tubulointerstitial structures. Transitioning to the center of the image is the mesangial stalk with mesangial cell hyperplasia (yellow) and mesangial expansion (pink), with loss of foot processes of the (blue) podocyte (also termed visceral epithelium) and increasing thickness of the glomerular basement membrane (BM) (red). Right: Increased capillary glomerular BM thickening (red) with atrophic podocytes and loss of foot processes of the podocyte (blue) to the capillary glomerular endothelial cell. Also depicts the tubulointerstitial fibrosis with expansion of the peritubular (blue) extracellular matrix (fibrosis), with an increased thickening of the tubular BM (red). Just below the efferent (blue) arteriole is depicted hyaline arteriolosclerosis and just above the afferent arteriole (red) is depicted hyperplastic arteriolosclerosis with its characteristic onion skin-like changes. The thickened BMs, arteriolar changes, and the mesangial expansion all are periodic acid-Schiff +, hyaline staining, and contain large amounts of type IV collagen with increased laminin and fibronectin with concurrent decreased amounts of heparan sulfate proteoglycan (perlecan).

Glomerulosclerosis and atherosclerosis share many remodeling commonalities and have been previously compared.36 Since most patients who have diabetic nephropathy and CKD die of CVD, we must be aware of this parallel occurrence and treat both conditions in this high-risk patient population according to accepted guidelines. Within the glomerulus, there is also a differential expression of PGs—as in the intima. The heparan sulfate PGs are decreased and the chondroitin sulfate PGs are increased, with an associated loss of filtering function, resulting in an increased permeability to plasma proteins, resulting in turn in microalbuminuria and macroalbuminuria, which are associated with an increased risk of macrovascular disease and CV events. Microalbuminuria and macroalbuminuria reflect a generalized endotheliopathy associated with endothelial dysfunction.

Early Renal Changes in the Zucker Obese Model. The Zucker obese rat parallels the human CMS patient very closely and is characterized by IR, the multiple A-FLIGHT-U metabolic toxicities, ROS, hypertension, impaired glucose tolerance, and the gradual development of overt T2DM. These changes are associated with significant remodeling of the glomerular filtration barrier interface (specifically the BM and podocyte) (Figure 10). The renal glomerular podocyte is a specialized endothelial pericyte and demonstrates the important supporting role of the pericyte throughout the systemic capillary beds in each of the end-organ complications (Table II).

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Figure 10. Podocyte and basement membrane (BM) remodeling in the 14-week-old Zucker obese rat kidney. A) Healthy nonobese Sprague-Dawley rat glomerulus. A healthy filtration barrier is demonstrated with endothelial cell, BM, and the podocyte slit diaphragm (30–40 nm) evident. Original magnification ×10,000. B) Zucker obese rat model of the cardiometabolic syndrome. Note the remodeled podocyte foot process morphology including effacement and flattening on the glomerular BM. Also note filtration slit diaphragm loss, BM thickening, varying electron-dense vacuoles containing lipid and protein. Original magnification ×10,000. DN=diabetic nephropathy

Microalbuminuria may be thought of as a manifestation of generalized endothelial dysfunction in both the systemic vasculature and in the renal glomerulus, resulting in microalbuminuria in the CMS. The microvascular leakage of proteins (specifically microalbumin) portends an increased risk for the future development of CKD, diabetic nephropathy, CVD, and stroke.38 The link between CMS and CKD is discussed in detail in the article by Bakris and colleagues in this issue of JCMS.

Conclusion

  1. Top of page
  2. Abstract
  3. Myocardial Redox Stress and Remodeling in CMS
  4. Metabolic Hepatopathy: NAFLD/NASH
  5. Intimal Redox Stress and ECM Remodeling in Vasculature
  6. Pancreatic Islet Redox Stress, Islet Amyloid, and ECM Remodeling
  7. Neural Redox Stress and Remodeling
  8. Endothelial Redox Stress and Remodeling
  9. Renal Redox Stress and Remodeling
  10. Conclusion
  11. References

The CMS is a construct associated with a complicated mosaic of multiple metabolic toxicities resulting in the production of excessive ROS and endothelial dysfunction, which results in both cellular and ECM remodeling of the end-organs affected by CMS. If we use a global risk reduction approach utilizing the RAAS acronym (Table III) and treat to known established goals, we may be able to prevent, or at least delay, many of the complications associated with the MINER acronym. The combination of identifying and considering the myriad complications and the various therapeutic modalities will give the health care provider and the patient an opportunity to unravel this complicated mosaic of clinical clustering and metabolic toxicities in the CMS.

Table III.  The Renin-Angiotensin-Aldosterone System (RAAS) Acronym: Global Risk Reduction
RReductase inhibitors (3-hydroxy-3-methylglutaryl coenzyme A): lipoprotein modifying effects:
 [DOWNWARDS ARROW] Native low-density lipoprotein cholesterol (LDL-C) substrate and subsequent modified atherogenic LDL-C (oxidized-acetylated, glycated, glycoxidated, homocysteinylated, aggregated LDL-C)
 [DOWNWARDS ARROW] Triglycerides; [UPWARDS ARROW] high-density lipoprotein cholesterol, ameliorating endothelial cell dysfunction
 Restoring abnormal lipoprotein fractions [RIGHTWARDS ARROW][DOWNWARDS ARROW] oxidation-reduction (redox) and oxidative stress to arterial vessel wall, myocardium, and target organs
AAngiotensin II (Ang II) blockade
 Angiotensin-converting enzyme inhibitors (“prils”); angiotensin receptor blockers (“sartans”): both inhibit the effect of Ang II locally as well as systemically, moderating hemodynamic stress through their antihypertensive effect and the deleterious effects of Ang II on cells at the local level, [DOWNWARDS ARROW] the stimulus for superoxide production, [DOWNWARDS ARROW] the A-FLIGHT-U toxicities. Direct/indirect antioxidant effect within the arterial vessel wall and capillary; antioxidant effects
 Aspirin: antiplatelet, anti-inflammatory effects
 Adrenergic blockade: both p blockade and nonselective β blockade [DOWNWARDS ARROW] the elevated sympathetic stimulation in addition to their antihypertensive effects and blockade of prorenin [RIGHTWARDS ARROW] renin
 Amlodipine: calcium channel blockers (CCBs): dihydropyridine (DHP) and non-DHP CCBs: antihypertensive effects in addition to their direct and indirect anti-oxidant effects
AAggressive control of:
 Diabetes: to glycated hemoglobin of <7% (usually requires combination therapy with the use of insulin secretagogues, insulin sensitizers (thiazolidinediones), biguanides, α-glucosidase inhibitors, and ultimately exogenous insulin)36–38
 Hyperlipidemia: [DOWNWARDS ARROW] modified LDL-C, i.e., glycated/glycoxidated LDL-C. Improving endothelial cell dysfunction. Also [DOWNWARDS ARROW] glucotoxicity and the oxidative-redox stress to the intima and pancreatic islet
 Blood pressure: usually requires combination therapy including thiazide diuretics to attain Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines
 Homocysteine: using folic acid with its associated additional positive effect on recoupling the endothelial NO synthase (eNOS) reaction by restoring the activity of the tetrahydrobiopterin (BH4) cofactor to run the eNOS reaction and once again produce endothelial NO
SStatins: improving plaque stability (pleiotropic effects) independent of cholesterol lowering. Ameliorating endothelial cell dysfunction. Direct/indirect antioxidant, anti-inflammatory effects within the islet and the arterial vessel wall, promoting stabilization of the unstable, vulnerable islet and the arterial vessel wall
 Style: lifestyle modification: lose weight, exercise (cardiac rehabilitation), and change eating habits
 Stop smoking
[DOWNWARDS ARROW]=decreasing; [UPWARDS ARROW]=increasing; [RIGHTWARDS ARROW]=leading to

Acknowledgments and disclosure: The authors wish to acknowledge the Electron Microscopy Core Facility at the University of Missouri-Columbia, Columbia, MO and Cheryl A. Jensen, electron microscopy specialist, for excellent help with the preparation of transmission electron micrographs. A part of this work was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute Grant RO1 HL-63904-01 and a Department of Veterans Affairs Merit Review (Dr. Sowers). Dr. Sowers has received grants from AstraZeneca and Novartis, and is a speaker for Bristol-Myers Squibb and Novartis.

References

  1. Top of page
  2. Abstract
  3. Myocardial Redox Stress and Remodeling in CMS
  4. Metabolic Hepatopathy: NAFLD/NASH
  5. Intimal Redox Stress and ECM Remodeling in Vasculature
  6. Pancreatic Islet Redox Stress, Islet Amyloid, and ECM Remodeling
  7. Neural Redox Stress and Remodeling
  8. Endothelial Redox Stress and Remodeling
  9. Renal Redox Stress and Remodeling
  10. Conclusion
  11. References
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