Gender Difference in the Pathophysiology of Hypertension

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1 Gender Difference in the Pathophysiology of Hypertension Regional Cardiovascular Center Chungbuk National University Hospital Kyung-Kuk Hwang

2 Complex trait determined by gene & environment Blood pressure (BP) : complex trait regulated by an integrated network of physiological pathways including volume status, cardiac contractility and vascular resistance through renal, neural or endocrine systems. Hypertension (HT) : combination of genetic and environmental factors Heritability of BP : fraction of BP variance contributed by genetic determinants - 31~68 % Dietary sodium intake : most common and important environmental risk factor for HT? Gender difference in HT [Kelly TN. Progress in Molecular Biology. 2012]

3 Gender differences in blood pressure (BP) ** P<0.01 Age (n) 20 weeks N=8 12 weeks N=10 45 weeks N=10 1 year N=7 72-h radiotelemetry 1-h ear artery 72-h carotid artery catheter [Sandberg K Biology of Sex Differences 2012]

4 Gender differences in HT: experimental HT models Ang II infusion aldosterone infusion L-NAME-treated intrauterine growth restriction intrauterine nutrition restriction New Zealand genetically hypertensive rat [Sandberg K Biology of Sex Differences 2012]

in male but not female mice Gonadectomy : attenuates ANG II-induced HT in male

5 Gender difference in angiotensin II-induced HT MAP before and during infusion of angiotensin II (ANG II, 800 ng/kg per min) low-dose infusion of ANG II : BP in male but not female mice Gonadectomy : attenuates ANG II-induced HT in male augments ANG-induce HT in female mice [Xue B. et al Braz J Med Biol Res 2007]

6 Effect of gonadectomy on BP: experimental HT models Effect of Sex-hormone milieu [Sandberg K Biology of Sex Differences 2012]

7 Pathophysiology of hypertension female hypertension Genetic determinant : X vs Y chromosome Sex hormone-related response in BP control and/or regulating system Brain SNS RAS Inflammatory Immunity Renal Vascular system SMC, Endothelial cell vasomotor tone Environment-related response in BP control and/or regulating system

8 Pathophysiology of hypertension female hypertension Genetic determinant : X vs Y chromosome Sex hormone-related response in BP control and/or regulating system Brain SNS RAS Inflammatory Immunity Renal Vascular system SMC, Endothelial cell vasomotor tone Environment-related response in BP control and/or regulating system

9 ? Gender difference (X versus Y chromosome)

10 Gender differences in biology Gender differences in biology : arise from differences in sex chromosome dosage (2X vs. 1X or 0Y vs. 1Y) 2X vs. 1X 0Y vs. 1Y SRY (Sex-determining Region of the Y chromosome)?? located on X ACE 2 ATGR II RENBP Sry located on Y - transcription factor - causes differentiation of testes and a rise in testosterone levels in utero [Sandberg K. Biology of Sex Differences. 2012]

11 Generation of the four core genotype (FCG) - Sry gene was spontaneously deleted from Y chromosome through natural mutation (Y - ) : does not develop testes, deveolp ovary express female gonadal hormone - Sry gene was inserted to an autosome, creating XY - Sry and XXSry express male gonadal hormone Breeding XX females with XY - Sry males produces the four core genotype 1 XY - female 2 XX female 3 XY - Sry male 4 XXSry male. [Sandberg K. Biology of Sex Differences. 2012]

12 Isolated sex chromosome effect from gonadal sex effects in Ang II-induced HT model Magnitude of the hypertension - greater in gonadectomized XX mice compared to gonadectomized XY mice regardless of whether the mice were born male or female [Sandberg K. Biology of Sex Differences. 2012]

13 Y chromosome contributes around mmhg arterial pressure BP in hypertensive rats following introgression of Y chromosome from a normotensive rat strain in BP in normotensive rats following introgression of the Y chromosome from a hypertensive rat strain [Negrin CD, Hypertension, 2001]

14 Regulation of RAS gene by SRY Sry expression vectors were co-transfected into CHO cells with luciferase reporter constructs containing promoters of angiotensinogen(agt), renin, ACE and ACE Sry3: Control Agt Renin ACE ACE2 activity of renin, angiotensinogen and ACE promoters activity of ACE2 [ Milsted A, J Hypertens. 2010]

15 Three key findings in animal study Gonadectomized XX mice showed a greater pressor response to chronic Ang II infusion than gonadectomized XY mice, independent of prior sex hormone and gonadal phenotype sex chromosome complement significantly influences arterial pressure responses to Ang II, independent of gonadal phenotype Y chromosome contributes around mmhg arterial pressure Reduction arterial pressure in hypertensive rats following introgression of Y chromosome from a normotensive rat strain. Increase in blood pressure in normotensive rats following introgression of the Y chromosome from a hypertensive rat strain [Ely DL, Hypertension. 1990, Negrin CD, Hypertension. 2001] Sry gene, located on the Y chromosome - upregulates promoter activity of angiotensinogen, renin and ACE in vitro - decreases promoter activity of ACE2 in vitro [ Milsted A, J Hypertens. 2010]

16 X chromosome AT2R and ACE2 genes are located on the X chromosome - suggesting a greater role of these depressor RAS arm components in females Gender differences in polymorphisms (SNPs) of the RAS Gender-specific associations between HT and RAS gene polymorphisms - males: ACE and AT1R gene polymorphisms are significantly associated - females: angiotensinogen and ACE2 gene polymorphisms are associated

17 Gene reported: RAS system Gene symbol Gene Chr Physical position (bp) Renin angiotensin aldosterone system ACE Angiotensin-converting enzyme ACE2 Angiotensin-converting enzyme 2 X AGT Angiotensinogen AGTR1 Angiotensin II receptor, type AGTR2 Angiotensin II receptor, type 2 X CYP11B1 Cytochrome P450, family 11, subfamily B, polypeptide CYP11B2 Aldosterone synthase HSD11B2 Hydroxysteroid (11- ) dehydrogenase type RENBP Renin-binding protein X

18 Pathophysiology of hypertension female hypertension Genetic determinant : X vs Y chromosome Sex hormone-related response in BP control and/or regulating system Brain SNS RAS Inflammatory Immunity Renal Vascular system SMC, Endothelial cell vasomotor tone Environment-related response in BP control and/or regulating system

19 Sex steroid hormones and their receptors [Medelsohn ME. Science. 2005]

20 Sex steroid hormone receptor signaling SSH: Sex steroid hormone 2 SSHRs participate in rapid cellular activation pathways that at least initially do not alter gene expression; eg) enos SSHR: Sex steroid hormone receptor CoA: coactivator Rapid signaling pathways can converge on genomic pathways, activating transcription of genes lacking SSH response elements CoR: corepressor NHR: non-sshr nuclear receptors SSHRE : SSH response element 1 co-regulatory proteins to alter transcription: cell-specific expression of co-regulatory protein tissue specific and temporal regualtion of SSHR-mediate transcription [Medelsohn ME. Science. 2005]

Sex steroid hormone receptor signaling 5 Genetic SSHR variants influence individual responses to SSHs 3 ER and PR in vascular cells also can be activated in the absence of ligand by growth factor

21 Sex steroid hormone receptor signaling 5 Genetic SSHR variants influence individual responses to SSHs 3 ER and PR in vascular cells also can be activated in the absence of ligand by growth factor pathways 4 SSHRs cross-regulate expression of one another in vascular cells NHR: non-sshr nuclear receptors 6 SSHRs can regulate non-ssh nuclear receptors such as the peroxisome proliferator-activatedivated receptor a (PPARα), and the liver X receptors (LXRs), which govern metabolic pathways directly relevant to CVD

22 Central effect of the ER antagonist Central infusion of the ER antagonist ICI 182,780 (1.5μg/kg per day) facilitates ANG II-induced HT in female SD rats. OVX ovariectomized E2 protects against ANG II induced HT in females via actions on the ERα [Xue B. et al Braz J Med Biol Res 2007]

Central effect of the androgen antagonist Central infusion of androgen receptor blocker, flutamide, attenuates ANG II-induced HT in female SD rats.

23 Central effect of the androgen antagonist Central infusion of androgen receptor blocker, flutamide, attenuates ANG II-induced HT in female SD rats. ANG II, 800 ng kg/kg/day infusion castrated (Cas), Central flutamide (Flu, 0.8 mg/kg/day) Androgen receptor might mediate ANG II induced HT in male [Xue B et al FASEB J 2004]

activation is required for ANG II-induced hypertension in males

24 Reactive oxidative stress/n NOS Central infusion of tempol, SOD mimetic, blocks ANG II induced HT in male mice : central ROS activation is required for ANG II-induced hypertension in males ethidium fluorescence- ROS generation [Xue B. et al Braz J Med Biol Res 2007]

25 [Xue B. et al Braz J Med Biol Res 2007]

26 Central effect of sex hormones Sex hormones (E2, androgen) and their central receptors - modulate ANG II-induced HT - interactions sex hormones and ROS/NO within circumventricular organs significantly influence ANG II-induced HT Links b/t NO, ROS, sex hormones and ANG II in neurohumoral activation - sex hormones, ANG II, NO, and ROS regulate autonomic function. Both E2 and testosterone are hypothesized to modulate the effects of AT1R activation by modulating the ROS/NO balance

27 Renin-angiotensin system (RAS): Novel RAS Novel puzzle RAS : classical simplified RAS has turn to a very complex network Modulation of the RAS - key approach to reduce deleterious properties of over-activated RAS in HT Gender difference in (novel puzzle) RAS Major gender-related differences exist in the RAS because of differential modulation of this system by sex hormones

28 Tonin, Cathepsin G Unger T. Eur Heart J. 2011: 32, Renin Chymase AMPA AMPM Angiotensinogen Angiotensin I (1-10) Angiotensin II (1-8) Angiotensin III (2-8) Angiotensin IV (3-8) ACE2 ACE NEP ACE2 ACE Angiotensin (1-9) Angiotensin (1-7) RR MAS AT 2 R AT 1 R AT 4 R Protein synthesis Anti-apoptosis proliferation Vasodilation Anti-fibrosis Apoptosis Natriuresis Anti-inflammation Vasoconstriction Collagen synthesis ROS gheneration Na and water retension Inflammation

29 RAS: New pathway Depressor arm of the RAS (ACE2/Ang(1-7)/MasR and AT2R) : counter-regulates the classical ACE/AngII/AT1R pathway Iwai M. Hypertension Res. 2009: 32,

30 Postnatal ontogeny of angiotensin receptors and ACE2 in male and female SD rats Relative AT1aR mrna gene expression AT1aR expression : 4-fold greater in kidney than left ventricle [Sampson AK et al Gend Med 2011]

31 Postnatal ontogeny of angiotensin receptors and ACE2 in male and female SD rats Relative AT1bR mrna gene expression AT1bR expression : 8-fold greater in kidney than left ventricle Males : significant decrease Female rats : higher AT1bR expression in adulthood than males [Sampson AK et al Gend Med 2011]

32 AT2R and MasR expression AT2R MasR mrna [Sampson AK et al Gend Med 2011]

33 ACE2 expression ACE2 P=0.006 [Sampson AK et al Gend Med 2011]

34 Mean arterial pressure in postnatal day 110 female and male Expression of AT2R, MasR, and ACE2 : significantly greater in adult female kidneys compared with male kidneys [Sampson AK et al Gend Med 2011]

35 Estrogen and RAS Evidences indicate that estrogen regulates all components of the RAS Estrogen - angiotensinogen synthesis, renin and ACE synthesis in postmenopausal women [Schunkert H et al. Circulation. 1997] - AT1R expression, AT2R expression in target tissue at rat ovariectomy decreased AT2R expression [Baiardi G et al. Regul Pept. 2005] estrogen replacement increased AT2R expression in rat kidney testosterone amplified the pressor RAS in males [Miyata N et al. Am J Physiol. 1999] [Ozono R et al. Hy[ertension. 1997] [Reckelhoff JF. Gend Med. 2008]

36 Estrogen in animal study Chronic low-dose infusion of Ang II dose caused increase BP in males arterial pressure in female rats (~10 mmhg) [Jones ES et al. Pharmarcol The. 2008] Action of Ang II to decrease arterial pressure in female rats - mediated via the AT2R - estrogen-dependent [Sampson AK et al. Am J Physiol Regul Integr Comp Physiol. 2012] Female mice have an attenuated response to Ang II infusion - compared to male wild-type - female AT2R knockout mice [Broen RD. Hypertension. 2012] AT2R plays an enhanced role in regulating arterial pressure in females

37 Testosterone and RAS Role of testosterone in arterial pressure regulation - well documented in testosterone removal/replacement studies Arterial pressure - reduced after castration restored after testosterone replacement in mulitiple animal models SHR [Chen YF. Life Sci. 1991, Ganton U, J Hpertens 1989, Iam SG, J lab Clin Med 1977] Dahl-salt-sensitive and Goldblatt hypertensive animal models [Rowland NE. Clin Exp Hypertens 1992, Rettig R Hypertension 1990]

38 Testosterone in animal study Testosterone directly interacts with RAS - angiotensinogen gene expression, renin activity and AT1R expression [Chen YF, Hypertension. 1992] [Ellison KE, J Clin Invest. 1989] [Johnston CI, Kidney Int Suppl. 1993] Castration : higher plasma renin levels in males is lowered - testosterone replacement : renin level is increased [Kienitz T, Kidney Blood Press Res, 2008] ACE inhibition in male and female SHRs - abolishes the sex difference in arterial pressure Testosterone interacts with the RAS, increasing activation of the classical pathway resulting in AT1R activation by Ang II.

39 Clinical data Congestive heart failure survival rates - better in women treated with ARB (AT2R-mediated contribution) compared with ACE inhibitors, and the reverse is true for males : 10,223 women (8627 ACEI, 1596 ARB) and 9475 men (8484 ACEI, 991 ARB) women on ARBs, better 90-day survival than ACEI (adjusted HR 0.69) no difference in survival in men prescribed ARBs compared to ACEI (HR 1.10) [Hudson M. Eur J Heart Fail. 2007] Renal response to Ang II infusion - attenuated more in women than in men (suggested AT2R-related effect) [Miller JA. J Am Soc Nephrol. 2006] [Silbiger S. Nat Clin Prat 2007] [Miller JA Kidney In 1999] These strongly support a greater role for the depressor arm of the RAS in women than men

40 Clinical studies, However Some studies have reported gender differences in response to inhibition of the RAS, others have not Many clinical trials are not powered to detect such differences because of the lower enrolment of women However, animal studies have provided stronger evidence of genderrelated differences in the RAS, suggesting that further clinical studies are warranted. ACE2/Ang(1 7)/MasR axis elicits gender-specific effects in kidney

41 Effects of estrogen on the vasculature - RAS Estrogen regulates vascular function - RAS, Endothelin, Reducing oxidative stress 17β-estradiol: AT1R mrna expression in cultured vascular SMCs Ovariectomized rats - AT1R mrna expression in aorta after 17β-estradiol repalcement: AT1R mrna expression in aorta [Nickenig G, Circulation. 1998] Replacement of 17β-estradiol in ovariectomized rats - plasma ACE activity and circulating angiotensin II level [Brosnihan KB, Am J Physiol. 1997] 17β-estradiol-mediated reduction in expression of AT1R and ACE activity - prevents some of the vasoconstrictor effects of RAS in the vasculature

42 Effects of estrogen on the vasculature : ET, SOD Estrogen modulate endothelin (ET) level and activity ETA receptor- vasoconstrictor, ETB receptor- vasodilation In DOCA-salt hypertensive rats -17β-estradiol : ET synthesis, attenuates endothelial dysfunction [David FL, Hypertension. 2001] In human - ratio of ETA to ETB receptors in premenopausal women : vasodilatory effects via ETB receptors [Ergul A, J Pharmacol Exp Ther. 1998] - high levels of estrogens: associated with reduced levels of ET [Polderman KH, Ann Intern Med. 1993] - hormone therapy in postmenopausal women : plasma ET level [Ylikorkala O, J Clin Endocrinol Metab. 1995] Estrogens protect the vasculature via antioxidant activity - 17β-estradiol induces activation of SOD [Inarrea P, Free Radic Biol Med. 2011]

43 Pathophysiology of hypertension female hypertension Genetic determinant : X vs Y chromosome Sex hormone-related response in BP control and/or regulating system Brain SNS RAS Inflammatory Immunity Renal Vascular system SMC, Endothelial cell vasomotor tone Environment-related response in BP control and/or regulating system

44 Effect of dietary sodium on the gender differences in MAP in the DS rat difference in MAP b/t males and females in DS rat as a function of dietary sodium [Sandberg K Biology of Sex Differences 2012]

45 Gene reported: associated with BP salt sensitivity Gene symbol Gene Chr Physical position (bp) Renin angiotensin aldosterone system ACE Angiotensin-converting enzyme I/D ACE2 Angiotensin-converting enzyme 2 Associated gene variants X rs ; rs ; rs ; rs ; rs ; rs AGT Angiotensinogen rs5050; rs5051; rs699 AGTR1 Angiotensin II receptor, type rs ; rs ; rs ; Rs AGTR2 Angiotensin II receptor, type 2 X rs CYP11B1 Cytochrome P450, family 11, subfamily B, polypeptide NA CYP11B2 Aldosterone synthase rs ; intron 2 conversion HSD11B2 Hydroxysteroid (11- ) dehydrogenase type rs ; rs ; rs5479; rs ; CA repeat RENBP Renin-binding protein X rs ; rs ; rs ; rs

46 Sex and sex hormone vs Stress Responses [Retgitz-Zrosek, Hypertension, 2012]

47 Summary: Gender difference in HT Genetic determinant : X vs Y chromosome Up to now, Yes! From FCG study : sex chromosome significantly influences arterial pressure responses to Ang II Y chromosome contributes around mmhg arterial pressure Sry gene, located on the Y chromosome : promoter activity of angiotensinogen, renin and ACE in vitro promoter activity of ACE2 in vitro AT2R and ACE2 genes are located on the X chromosome - suggesting a greater role of these depressor RAS arm components in females Gender-specific associations between HT and RAS gene polymorphisms - males: ACE and AT1R gene polymorphisms are significantly associated - females: angiotensinogen and ACE2 gene polymorphisms are associated

48 Summary: Gender difference in HT Sex hormone-related response in BP control and/or regulating system Brain SNS RAS Inflammatory Immunity Renal Vascular system SMC, Endothelial cell vasomotor tone Evidences indicate that estrogen regulates all components of the RAS Estrogen: depressor arm of the RAS (ACE2/Ang(1-7)/MasR and AT2R) - counter-regulates the classical ACE/AngII/AT1R pathway

49 Summary: Gender difference in HT Environment-related response in BP control and/or regulating system Salt sensitivity Stress-response

50 Conclusion Gender differences exist in the regulation of BP Based on animal studies, these gender differences can be derived from - sex chromosome - sex hormone-related response in BP control and/or regulating system - environment-related response in BP control and/or regulating system Understanding intrinsic gender differences in HT provide the rationale for treating men/women with anti-ht regimens that reach maximal optimization in both sexes Understanding intrinsic gender differences in cardiovascular function has exposed new therapeutic targets

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