Original articleElevated 20-HETE in metabolic syndrome regulates arterial stiffness and systolic hypertension via MMP12 activation
Introduction
Large artery stiffness is a major risk factor for hypertension, stroke and myocardial infarction [1]. Structural properties of large arteries, medial thickness and composition of the extracellular matrix (ECM), are the main determinants of large artery stiffness [2].
Despite the significant contribution of the ECM to increased blood pressure development and maintenance, no currently available anti-hypertensive therapy directly targets the ECM, although some (e.g. angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)) do affect it. Targeting elastin fiber integrity has been proposed as an effective therapy to specifically target systolic hypertension. Studies in elastin knockout mice have shown that its deficiency leads to a severe and fatal increase in systolic pressure, which is preceded by arterial stiffening, suggesting a causative role for elastin in maintenance of not only arterial compliance but also of normal systolic pressure [3].
Matrix metalloproteinase 12 (MMP12), one of the major elastin-degrading proteases, is secreted primarily from monocytes and neutrophils [4], but can also be made by synthetic vascular smooth muscle cells (VSMCs) [5]. Its upstream regulators are unknown. It has been implicated in chronic obstructive pulmonary disease and emphysema, atherosclerosis in type II diabetes, aneurysms, cancer and stiffening of femoral arteries in response to injury [[5], [6], [7], [8], [9]]. Its role in arterial stiffness in metabolic syndrome or hypertensive animals or humans has not been investigated. MMPs classically associated with the regulation of hypertension-induced arterial stiffness are MMP2 and MMP9, but their activity does not fully account for either large artery stiffness or systolic hypertension in animal models or humans [10].
20-hydroxyeicosatetraeonic acid (20-HETE) is synthesized from arachidonic acid by cytochrome P450 (CYP) [11]. In rats, CYP4A (A1, A2, A3, A8) and CYP4F (F1, F4) are the CYP isoforms which produce 20-HETE. 20-HETE is synthesized and released from many cell types including VSMCs [12], endothelial cells, neutrophils [13] and bone marrow cells [14].
The association with and causative role of 20-HETE in the development of hypertension is now well established. In the SHR rat, depletion of CYP4A decreased 20-HETE and significantly lowered mean arterial blood pressure [15]. Androgen-driven hypertension in mice and rats, the Cyp4a14 (−/−) androgen-dependent 20-HETE-mediated hypertension mouse model, the Cyp4a12 doxycycline inducible mouse model, and the Sprague-Dawley (SD) rat overexpressing CYP4A2 in the vascular endothelium exhibit increased 20-HETE production and hypertension [[16], [17], [18], [19]]. However, 20-HETE's role in the regulation of vascular structural remodeling is just emerging. Only recently, Schwartzman's group demonstrated that 20-HETE induced microvascular remodeling, which was only partially Ang II-dependent [20]. Furthermore, all previous studies evaluated the effect of 20-HETE manipulation only on mean arterial blood pressure (MABP). Moreover, because in normal, healthy animals 20-HETE is not produced in large arteries, all work focused on the role of small, resistance arteries and the contribution of myogenic tone to the regulation of systemic blood pressure. Therefore, nothing is known about the possible effect of 20-HETE in large arteries or on extracellular matrix (ECM) remodeling.
In this study, we explore a novel idea that, in the metabolic syndrome, 20-HETE specifically modulates systolic but not diastolic blood pressure, and that it does so by regulating large artery compliance, as a critical determinant of arterial stiffness, through regulating elastin degradation via MMP12 activation.
Section snippets
Animals
10–12 week old, male JCR:LA-cp (JCR; S. Proctor, University of Alberta, Edmonton, Canada) (650–700 g), spontaneously hypertensive obese (SHROB, Charles Rivers, Wilmington, MA) (650–700 g) and Sprague-Dawley (SD; Charles Rivers) (300–350 g) rats were used in all experiments. The JCR rat is a cross between the lean LA/N Zucker and the spontaneously hypertensive obese (SHROB) rat developed in the laboratory of Dr. Carl Hansen at the National Institutes of Health and sent to Drs. James C. Russell
CYP4A, CYP4F and 20-HETE are elevated in metabolic syndrome
CYP4A (4A1, 2, 3 and 8) and CYP4F (4F1 and 4) are the CYP isoforms expressed in rat which make 20-HETE; the rat expresses 4F5 and 6 but these two isoforms do not make 20-HETE [32]. Our results indicate that CYP4A and CYP4F are expressed in carotid arteries and aorta of JCR and SHROB but not of SD rats (~2 fold JCR vs. SD) (Figs. 1A and VIII, Supplement). By RT-PCR analysis, we have identified the CYP4A isoforms expressed in arteries of JCR and SD rats to be 4A2 and 4A3; whereas, 4A1 expression
Discussion
The most important findings in this study are: 1) that 20-HETE is highly elevated in large, conduit arteries of metabolic syndrome animals which correlates with increased elastin degradation, decreased large artery compliance and increased blood pressure in these animals, and 2) that 20-HETE antagonism reverses elastin degradation, restores large artery compliance and normalizes systolic but not diastolic blood pressure in the metabolic syndrome animals, and 3) that this effect is in part Ang
Sources of funding
NIH R01HL093052 (PR), NIH 1F31HL137356 (AS), P01HL034300 (MLS).
Disclosures
None.
Acknowledgments
The authors would like to acknowledge Dr. Alberto Nasjletti (Department of Pharmacology, New York Medical College) for critical review of the manuscript prior to submission.
References (94)
- et al.
Extracellular matrix alterations in hypertensive vascular remodeling
J. Mol. Cell. Cardiol.
(2010) - et al.
Modulation of erythropoiesis by novel human bone marrow cytochrome P450-dependent metabolites of arachidonic acid
Blood
(1991) - et al.
Therapeutic levels of human factor VIII and IX using HIV-1-based lentiviral vectors in mouse liver
Blood
(2000) - et al.
Expression and induction of CYP4F subfamily in human leukocytes and HL60 cells
Biochim. Biophys. Acta Mol. Cell Biol. Lipids
(2004) - et al.
Protective effect of 20-HETE analogues in experimental renal ischemia reperfusion injury
Kidney Int.
(2009) - et al.
Integrin cleavage facilitates cell surface-associated proteolysis required for vascular smooth muscle cell invasion
Int. J. Biochem. Cell Biol.
(2009) - et al.
TIMP3 interplays with apelin to regulate cardiovascular metabolism in hypercholesterolemic mice
Mol. Metab.
(2015) - et al.
Suppression of experimental abdominal aortic aneurysms in the rat by treatment with angiotensin-converting enzyme inhibitors
J. Vasc. Surg.
(2001) - et al.
Arterial stiffness in diabetes mellitus
Atherosclerosis
(2015) - et al.
Cytochrome P450-derived renal HETEs: storage and release
Kidney Int.
(1997)
Effects of chronic cytochrome P-450 inhibition on the course of hypertension and end-organ damage in Ren-2 transgenic rats
Vascul. Pharmacol.
Vascular actions of 20-HETE
Prostag. Oth. Lipid Mediat.
20-HETE and F2-isoprostanes in the metabolic syndrome: the effect of weight reduction
Free Radic. Biol. Med.
Arachidonic acid induces augmented vasoconstriction via cyclooxygenase 1 in the aorta from rats fed a high-fat diet
Prostaglandins Leukot. Essent. Fat. Acids
MMPs 2 and 9 are essential for coronary collateral growth and are prominently regulated by p38 MAPK
J. Mol. Cell. Cardiol.
The protective effect of HET0016 on brain edema and blood–brain barrier dysfunction after cerebral ischemia/reperfusion
Brain Res.
Arterial stiffness and hypertension: chicken or egg?
Hypertension
Elastin in large artery stiffness and hypertension
J. Cardiovasc. Transl. Res.
Remote exosites of the catalytic domain of matrix metalloproteinase-12 enhance elastin degradation
Biochemistry
Matrix metalloproteinase-12 is an essential mediator of acute and chronic arterial stiffening
Sci. Rep.
Matrix metalloproteinases in destructive lung disease
Matrix Biol.
Elevated plasma levels of MMP-12 are associated with atherosclerotic burden and symptomatic cardiovascular disease in subjects with type 2 diabetes
Arterioscler. Thromb. Vasc. Biol.
Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms
J. Clin. Invest.
Knockdown of MMP12 inhibits the growth and invasion of lung adenocarcinoma cells
Int. J. Immunopathol. Pharmacol.
Matrix metalloproteinase 2 and 9 dysfunction underlie vascular stiffness in circadian clock mutant mice
Arterioscler. Thromb. Vasc. Biol.
20-HETE and blood pressure regulation
Cardiol. Rev.
Cat cerebral arterial smooth muscle cells express cytochrome P450 4A2 enzyme and produce the vasoconstrictor 20-HETE which enhances L-type Ca2+ current
J. Physiol.
20-Hydroxyeicosatetraenoic acid synthesis is increased in human neutrophils and platelets by angiotensin II and endothelin-1
Am. J. Physiol. Heart Circ. Physiol.
Treatment with tin prevents the development of hypertension in spontaneously hypertensive rats
Science
Mouse Cyp4a isoforms: enzymatic properties, gender- and strain-specific expression, and role in renal 20-hydroxyeicosatetraenoic acid formation
Biochem. J.
Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE
Am. J. Physiol. Ren. Physiol.
Vascular cytochrome P450 4A expression and 20-hydroxyeicosatetraenoic acid synthesis contribute to endothelial dysfunction in androgen-induced hypertension
Hypertension
Androgen-sensitive hypertension associates with upregulated vascular CYP4A12-20-HETE synthase
J. Am. Soc. Nephrol.
Angiotensin II receptor blockade or deletion of vascular endothelial ACE does not prevent vascular dysfunction and remodeling in 20-HETE-dependent hypertension
Am. J. Phys. Regul. Integr. Comp. Phys.
Cardiovascular function in male and female JCR:LA-cp rats: effect of high-fat/high-sucrose diet
Am. J. Physiol. Heart Circ. Physiol.
Animal models of coronary heart disease
J. Biomed. Res.
Glucose tolerance, lipids, and GLP-1 secretion in JCR:LA-cp rats fed a high protein fiber diet
Obesity (Silver Spring)
Hypertension is a major contributor to 20-hydroxyeicosatetraenoic acid-mediated kidney injury in diabetic nephropathy
J. Am. Soc. Nephrol.
Increased MMP8 and 12 activation correlates with elevated endostatin and angiostatin and impaired coronary collateral growth in the metabolic syndrome
FASEB J.
Restoration of coronary collateral growth in the Zucker obese rat: impact of VEGF and ecSOD
Basic Res. Cardiol.
Induction of angiotensin-converting enzyme and activation of the renin-angiotensin system contribute to 20-hydroxyeicosatetraenoic acid-mediated endothelial dysfunction
Arterioscler. Thromb. Vasc. Biol.
Androgen-dependent hypertension is mediated by 20-hydroxy-5,8,11,14-eicosatetraenoic acid-induced vascular dysfunction: role of inhibitor of kappaB kinase
Hypertension
Vascular endothelial growth factor is required for coronary collateral growth in the rat
Circulation
Redox-sensitive Akt and Src regulate coronary collateral growth in metabolic syndrome
AJP Hear Circ. Physiol.
Catalytic activity and isoform-specific inhibition of rat cytochrome p450 4F enzymes
J. Pharmacol. Exp. Ther.
Cytochrome P -450 4A isoform expression and 20-HETE synthesis in renal preglomerular arteries
Am. J. Physiol. Ren. Physiol.
Elevated 20-HETE impairs coronary collateral growth in metabolic syndrome via endothelial dysfunction
Am. J. Physiol. Heart Circ. Physiol.
Cited by (23)
Bioactive lipid mediators in plasma are predictors of preeclampsia irrespective of aspirin therapy
2023, Journal of Lipid Research20-Hydroxyeicosatetraenoic acid (20-HETE): Bioactions, receptors, vascular function, cardiometabolic disease and beyond
2023, Advances in PharmacologyDifferential contribution of renal cytochrome P450 enzymes to kidney endothelial dysfunction and vascular oxidative stress in obesity
2022, Biochemical PharmacologyCitation Excerpt :On the other hand, 20-HETE has been reported to underlie diabetes and obesity-related cardiovascular and metabolic disorders and increased circulating and adipose levels of 20-HETE have been involved in high fat diet (HFD)-induced obesity, impaired insulin signalling and insulin resistance [17]. Moreover, highly elevated levels of 20-HETE in large conduit arteries have been associated with impaired elastin degradation and artery compliance, and increased blood pressure in animal models of metabolic syndrome [18], and also in metabolic syndrome-associated coronary endothelial dysfunction [19]. In the kidney, H2O2 derived from endothelial CYP2C11 and CYP2C23 epoxygenases contributes to the EDH-type vasodilator responses of preglomerular arteries [9].
Dietary flaxseed reduces Myocardial Ischemic Lesions, improves cardiac function and lowers cholesterol levels despite the presence of severe obesity in JCR:LA-cp Rats
2021, Journal of Nutritional BiochemistryCitation Excerpt :Furthermore, in the Hunter et al. study [21], no data on SBPs and DBPs were reported, but only in vitro estimates of MABPs using pressure myography, which is not as reliable an estimate of physiological BP. Finally, the shorter duration of the study (2 weeks) in the work by Soler et al. [23] could also contribute to the observed dissimilarity. Our study aligns with earlier work [42–44] that JCR:LA-cp rats do not have hypertension despite the obesity.
20-HETE interferes with insulin signaling and contributes to obesity-driven insulin resistance
2021, Prostaglandins and Other Lipid MediatorsMMP-12 as a potential biomarker to forecast ischemic stroke in obese patients
2020, Medical Hypotheses