BADERC- Gordon Williams

Gordon Williams, M.D.

Genetic Basis of Cardiovascular Risk in Diabetes Mellitus

The primary thrust of our research group is to define the genetic and mechanistic components underlying the variability of cardiovascular risk in diabetes mellitus. Because of the nature of the cardiovascular complications, residing primarily in individuals with type II diabetes, our clinical research studies are primarily focused on that group. Our currently NIH funded patient-oriented research program is outlined below:

The renin-angiotensin system (RAS) profoundly influences vascular responsiveness, cardiovascular remodeling, and plasminogen activator-inhibitor-1 (PAI-1) production. Further, aldosterone can modify the actions of the RAS on these target tissues, e.g., it modulates AngII receptor expression, enhances collagen formation and fibrosis and modifies PAI-1 production. Hyperglycemia and insulin also can modify these systems. Therefore, the RAS, hyperinsulinemia all may play substantial roles in mediating the adverse vascular (pressor, cardiac and atherosclerotic) complications in diabetes mellitus (DM). Variations in the occurrence of these complications may be secondary not only to the control of glucose and the level of exogenous and/or endogenous insulin, but also to variations in the functions of critical genes in the diabetic population. Our overall hypothesis is that in DM it is hyperinsulinemia and hyperglycemia in combination with differences in the specific alleles of the genes of the renin-angiotensin and PAI-1 systems that predispose the individual to vascular complications. To evaluate the hypothesis, we will address four Specific Aims:

1) To determine the relationship between angiotensinogen (AGT) genotype and hypertension in DM;

2) To test the hypothesis that variation in the pressor and hemodynamic responses to AngII in DM is mediated by variations in the genetic environment, specifically, the AGT and angiotensin converting enzyme (ACE) genes;

3) To determine the relationships between PAI-1 levels and insulin resistance and its response to insulin and AngII and to correlate these with PAI-1 and AGT genotypes; and

4) To assess the influence of hyperglycemia on vascular function and PAI-1 levels. To accomplish these goals, we will study normal subjects and patients with DM in the controlled environment of a General Clinical Research Center. Pressor and renal hemodynamic responses will be determined. The responsiveness of PAI-1 to AngII and insulin infusions, low salt diet and ACE inhibition will be assessed. Each subject’s alleles at the AGT, ACE and PAI-1 loci will be determined. It is anticipated that the results of these studies will clarify the potential role of the RAS and hyperglycemia in mediating the vascular and atherosclerotic (via its effect on PAI-1 production and release) complications of DM. An additional benefit derived from these studies will be to provide clues as to the role of variations in the genetic environment of the systems noted above on the variable expression of these complications as indicated by changes in surrogate markers. With this information, specific preventive an therapeutic measures could then be tested as to their efficacy in retarding the development of these complications.

We plan to expand our program to assess cellular mechanisms similar to what we have done for hypertension. We use a rodent animal model that produces significant cardiac, renal and vascular damage in a 14-day period. This model can be used in animals who are genetically or chemically diabetic. Transgenic animals are not good animals to assess the role of similar factors that are defined above for our clinical program in the development of cardiovascular damage in diabetes.

References:

1. Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE. Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension 1998; 32:965-971.

2. Ferri C, Bellini C, Desideri G, Valenti M, DeMattia G, Santucci, Hollenberg NK, Williams GH Relationship between insulin resistance and non-modulating hypertension: linkage of metabolic abnormalities and cardiovascular risk. Diabetes 1999; 48:1623-1630.

3. Fisher NDL, Hurwitz S, Ferri C, Jeunemaitre X, Hollenberg NK, Williams GH. Altered adrenal sensitivity to angiotensin II in low-renin essential hypertension. Hypertension. 1999; 34:388-394.

4. Price DA, Porter LE, Gordon M, Fisher NDL, DeOliveira JMF, Laffel LMB, Passan DR, Williams GH, Hollenberg NK. The paradox of the low-renin state in diabetic nephropathy. J Am Soc Nephrol. 1999;10:2382-2391.

5. Giacche M, Vuagnat A, Hunt SC, Hopkins PN, Fisher NDL, Azizi M, Corvol P, Williams GH, Jeunemaitre X. Aldosterone stimulation by angiotensin II: influence of gender, plasma renin, and familial resemblance. Hypertension. 2000; 35:710-716.

6. Kusaka Y, Kelly RA, Williams GH, Kifor I. Coronary microvascular endothelial cells co-secrete angiotensin II and endothelin-1 via a regulated pathway. Am J Physiology 2000; 279: H1087-H1096.

7. Rocha R, Stier CT, Kifor I, Ochoa-Maya MR, Rennke HG, Williams GH, Adler G. Aldosterone: A mediator of myocardial necrosis and renal arteriopathy. Endocrinology 2000;141: 3871-3878.

8. Raji A, Williams GH, Jeunemaitre X, Hoplins PN, Hunt SC, Hollenberg NK, Seely EW. Insulin resistance in hypertensives: effect of salt sensitivity, renin status and sodium intake. J Hypertens 2001; 19: 99-105.

9. Brown NJ, Murphey LJ, Srikunma N, Koschachuhanan N, Williams GH, Vaughan DE. Interactive effect of PAI-1 4G/5G genotype and salt intake on PAI-1 antigen. Arterioscler Thromb Vasc Biol 2001; 21: 1071-1077.

10. Vuagnat A, Giacche M, Hopkins PN, Azizi M, Hunt SC, Vedie B, Corvol P, Williams GH, Jeunemaitre X. Blood pressure response to angiotensin II, low-density lipoprotein cholesterol and polymorphisms of the angiotensin II type 1 receptor gene in hypertensive sibling pairs. J Mol Med 2001; 79: 175-183.

11. Fisher ND, Hurwitz S, Jeunemaitre X, Price DA, Williams GH, Hollenberg NK. Adrenal response to angiotensin II in black hypertension: lack of sexual dimorphism. Hypertension 2001; 38: 373-378.

12. Grant FD, Romero JR, Jeunemaitre X, Hunt SC, Hopkins PN, Hollenberg NH, Williams GH. Low-renin hypertension, altered sodium homeostasis, and an alpha-adducin polymorphism. Hypertension 2002; 39: 191-196.

13. Hopkins PN, Hunt SC, Jeunemaitre X, Smith B, Solorio D, Fisher NDL, Hollenberg NK, Williams GH. Angiotensin genotype affects renal and adrenal responses to angiotensin II in essential hypertension. Circulation 2002; 105: 1921-1927.

14. Martinez DV, Rocha R, Matsumura M, Oestreicher E, Ochoa-Maya M, Roubsanthisuk W, Williams GH, Adler GK. Cardiac damage prevention by eplerenone: comparison with low sodium diet or potassium loading. Hypertension 2002; 39: 614-618.

15. Slim R, Torremocha F, Moreau T, Pizard A, Hunt SC, Vuagnat A, Williams GH, Gauthier F, Jeunemaitre X, Alhenc-Gelas F. Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity. J Am Soc Nephrol 2002; 13:968-976.

16. Fisher NDL, Hurwitz S, Jeunemaitre X, Hopkins PN, Hollenberg NK, Williams GH. Familial aggregation of low-renin hypertension. Hypertension 2002; 39:914-918.

17. Raji A, Seely EW, Bekins SA, Williams GH, Simonson D. Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients. Diabetes Care 2003; 26: 172-178.

18. Hollenberg NK, Price DA, Fisher NDL, Lansang MC, Perkins B, Gordon MS, Williams GH, Laffel LMB. Glomerular hemodynamics and the renin-angiotensin system in patients with type 1 diabetes mellitus. Kid Int: 2003; 63:172-178.

19. Williams JS, Williams GH. 50^th anniversary of aldosterone. J Clin Endo Metab 2003; 88:2364-2372.

20. Kosachunhanun N, Hunt SC, Hopkins PN, Williams RR, Jeaunemaitre X, Corvol P, Ferri C, Mortensen RM, Hollenberg NK, Williams GH. Genetic determinants of nonmodulating hypertension. Hypertension 2003:42






			Gordon Williams, M.D. Genetic Basis of Cardiovascular Risk in Diabetes Mellitus The primary thrust of our research group is to define the genetic and mechanistic components underlying the variability of cardiovascular risk in diabetes mellitus. Because of the nature of the cardiovascular complications, residing primarily in individuals with type II diabetes, our clinical research studies are primarily focused on that group. Our currently NIH funded patient-oriented research program is outlined below: The renin-angiotensin system (RAS) profoundly influences vascular responsiveness, cardiovascular remodeling, and plasminogen activator-inhibitor-1 (PAI-1) production. Further, aldosterone can modify the actions of the RAS on these target tissues, e.g., it modulates AngII receptor expression, enhances collagen formation and fibrosis and modifies PAI-1 production. Hyperglycemia and insulin also can modify these systems. Therefore, the RAS, hyperinsulinemia all may play substantial roles in mediating the adverse vascular (pressor, cardiac and atherosclerotic) complications in diabetes mellitus (DM). Variations in the occurrence of these complications may be secondary not only to the control of glucose and the level of exogenous and/or endogenous insulin, but also to variations in the functions of critical genes in the diabetic population. Our overall hypothesis is that in DM it is hyperinsulinemia and hyperglycemia in combination with differences in the specific alleles of the genes of the renin-angiotensin and PAI-1 systems that predispose the individual to vascular complications. To evaluate the hypothesis, we will address four Specific Aims: 1) To determine the relationship between angiotensinogen (AGT) genotype and hypertension in DM; 2) To test the hypothesis that variation in the pressor and hemodynamic responses to AngII in DM is mediated by variations in the genetic environment, specifically, the AGT and angiotensin converting enzyme (ACE) genes; 3) To determine the relationships between PAI-1 levels and insulin resistance and its response to insulin and AngII and to correlate these with PAI-1 and AGT genotypes; and 4) To assess the influence of hyperglycemia on vascular function and PAI-1 levels. To accomplish these goals, we will study normal subjects and patients with DM in the controlled environment of a General Clinical Research Center. Pressor and renal hemodynamic responses will be determined. The responsiveness of PAI-1 to AngII and insulin infusions, low salt diet and ACE inhibition will be assessed. Each subject’s alleles at the AGT, ACE and PAI-1 loci will be determined. It is anticipated that the results of these studies will clarify the potential role of the RAS and hyperglycemia in mediating the vascular and atherosclerotic (via its effect on PAI-1 production and release) complications of DM. An additional benefit derived from these studies will be to provide clues as to the role of variations in the genetic environment of the systems noted above on the variable expression of these complications as indicated by changes in surrogate markers. With this information, specific preventive an therapeutic measures could then be tested as to their efficacy in retarding the development of these complications. We plan to expand our program to assess cellular mechanisms similar to what we have done for hypertension. We use a rodent animal model that produces significant cardiac, renal and vascular damage in a 14-day period. This model can be used in animals who are genetically or chemically diabetic. Transgenic animals are not good animals to assess the role of similar factors that are defined above for our clinical program in the development of cardiovascular damage in diabetes. References: 1. Brown NJ, Agirbasli MA, Williams GH, Litchfield WR, Vaughan DE. Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension 1998; 32:965-971. 2. Ferri C, Bellini C, Desideri G, Valenti M, DeMattia G, Santucci, Hollenberg NK, Williams GH Relationship between insulin resistance and non-modulating hypertension: linkage of metabolic abnormalities and cardiovascular risk. Diabetes 1999; 48:1623-1630. 3. Fisher NDL, Hurwitz S, Ferri C, Jeunemaitre X, Hollenberg NK, Williams GH. Altered adrenal sensitivity to angiotensin II in low-renin essential hypertension. Hypertension. 1999; 34:388-394. 4. Price DA, Porter LE, Gordon M, Fisher NDL, DeOliveira JMF, Laffel LMB, Passan DR, Williams GH, Hollenberg NK. The paradox of the low-renin state in diabetic nephropathy. J Am Soc Nephrol. 1999;10:2382-2391. 5. Giacche M, Vuagnat A, Hunt SC, Hopkins PN, Fisher NDL, Azizi M, Corvol P, Williams GH, Jeunemaitre X. Aldosterone stimulation by angiotensin II: influence of gender, plasma renin, and familial resemblance. Hypertension. 2000; 35:710-716. 6. Kusaka Y, Kelly RA, Williams GH, Kifor I. Coronary microvascular endothelial cells co-secrete angiotensin II and endothelin-1 via a regulated pathway. Am J Physiology 2000; 279: H1087-H1096. 7. Rocha R, Stier CT, Kifor I, Ochoa-Maya MR, Rennke HG, Williams GH, Adler G. Aldosterone: A mediator of myocardial necrosis and renal arteriopathy. Endocrinology 2000;141: 3871-3878. 8. Raji A, Williams GH, Jeunemaitre X, Hoplins PN, Hunt SC, Hollenberg NK, Seely EW. Insulin resistance in hypertensives: effect of salt sensitivity, renin status and sodium intake. J Hypertens 2001; 19: 99-105. 9. Brown NJ, Murphey LJ, Srikunma N, Koschachuhanan N, Williams GH, Vaughan DE. Interactive effect of PAI-1 4G/5G genotype and salt intake on PAI-1 antigen. Arterioscler Thromb Vasc Biol 2001; 21: 1071-1077. 10. Vuagnat A, Giacche M, Hopkins PN, Azizi M, Hunt SC, Vedie B, Corvol P, Williams GH, Jeunemaitre X. Blood pressure response to angiotensin II, low-density lipoprotein cholesterol and polymorphisms of the angiotensin II type 1 receptor gene in hypertensive sibling pairs. J Mol Med 2001; 79: 175-183. 11. Fisher ND, Hurwitz S, Jeunemaitre X, Price DA, Williams GH, Hollenberg NK. Adrenal response to angiotensin II in black hypertension: lack of sexual dimorphism. Hypertension 2001; 38: 373-378. 12. Grant FD, Romero JR, Jeunemaitre X, Hunt SC, Hopkins PN, Hollenberg NH, Williams GH. Low-renin hypertension, altered sodium homeostasis, and an alpha-adducin polymorphism. Hypertension 2002; 39: 191-196. 13. Hopkins PN, Hunt SC, Jeunemaitre X, Smith B, Solorio D, Fisher NDL, Hollenberg NK, Williams GH. Angiotensin genotype affects renal and adrenal responses to angiotensin II in essential hypertension. Circulation 2002; 105: 1921-1927. 14. Martinez DV, Rocha R, Matsumura M, Oestreicher E, Ochoa-Maya M, Roubsanthisuk W, Williams GH, Adler GK. Cardiac damage prevention by eplerenone: comparison with low sodium diet or potassium loading. Hypertension 2002; 39: 614-618. 15. Slim R, Torremocha F, Moreau T, Pizard A, Hunt SC, Vuagnat A, Williams GH, Gauthier F, Jeunemaitre X, Alhenc-Gelas F. Loss-of-function polymorphism of the human kallikrein gene with reduced urinary kallikrein activity. J Am Soc Nephrol 2002; 13:968-976. 16. Fisher NDL, Hurwitz S, Jeunemaitre X, Hopkins PN, Hollenberg NK, Williams GH. Familial aggregation of low-renin hypertension. Hypertension 2002; 39:914-918. 17. Raji A, Seely EW, Bekins SA, Williams GH, Simonson D. Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients. Diabetes Care 2003; 26: 172-178. 18. Hollenberg NK, Price DA, Fisher NDL, Lansang MC, Perkins B, Gordon MS, Williams GH, Laffel LMB. Glomerular hemodynamics and the renin-angiotensin system in patients with type 1 diabetes mellitus. Kid Int: 2003; 63:172-178. 19. Williams JS, Williams GH. 50^th anniversary of aldosterone. J Clin Endo Metab 2003; 88:2364-2372. 20. Kosachunhanun N, Hunt SC, Hopkins PN, Williams RR, Jeaunemaitre X, Corvol P, Ferri C, Mortensen RM, Hollenberg NK, Williams GH. Genetic determinants of nonmodulating hypertension. Hypertension 2003:42