It is well known that vascular stiffness increases with aging, yet the mechanisms involved are poorly understood, potentially due, in part, to lack of appropriate models. Indeed, the majority of research in aging has been conducted in rodent models or in humans with associated diseases of aging, e.g., diabetes or atherosclerosis. The primate model is unique because it is phylogenetically closer to humans, yet does not have associated diseases of aging. Over the past funding period, we have developed this primate model and have uncovered novel preliminary data supporting the renewal application. Our preliminary data indicate that female monkeys appear relatively protected from the vascular changes associated with aging compared with males. There are major gender differences observed in the composition of the vascular wall with aging and also in response to sympathomimetic amines. Accordingly, one important theme in this proposal includes examination of gender differences during aging. We will examine three hypotheses 1) Vascular stiffness increases in old male monkeys, but is relatively protected in old female monkeys. However, importantly, our hypothesis is that increases in vascular stiffness cannot be ascribed entirely to changes in collagen and elastin. Therefore, we propose two novel hypotheses: a.) that one mechanism of increased vascular stiffness with age involves caveolin and microtubules polymerization; and B.) that in part the increase in vascular stiffness with age resides at the level of the smooth muscle cell. For these studies, vascular smooth muscle stiffness will be assessed using an atomic force microscope; 2) Differences in the pattern of the expression of genes could explain the gender differences involved in the development of vascular stiffness; and 3) Gender differences must exist in the pattern of expression of proteins that could explain the differences involved in the development of vascular stiffness. These hypotheses and aims will be investigated using a multidisciplinary approach to maximally utilize this novel primate model.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014121-10
Application #
7093186
Study Section
Special Emphasis Panel (ZRG1-ECS (03))
Program Officer
Dutta, Chhanda
Project Start
1996-09-30
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2007-07-31
Support Year
10
Fiscal Year
2006
Total Cost
$565,797
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Vatner, Dorothy E; Yan, Lin; Lai, Lo et al. (2015) Type 5 adenylyl cyclase disruption leads to enhanced exercise performance. Aging Cell 14:1075-84
Iwatsubo, Kosaku; Bravo, Claudio; Uechi, Masami et al. (2012) Prevention of heart failure in mice by an antiviral agent that inhibits type 5 cardiac adenylyl cyclase. Am J Physiol Heart Circ Physiol 302:H2622-8
Guellich, Aziz; Gao, Shumin; Hong, Chull et al. (2010) Effects of cardiac overexpression of type 6 adenylyl cyclase affects on the response to chronic pressure overload. Am J Physiol Heart Circ Physiol 299:H707-12
Depre, Christophe; Park, Ji Yeon; Shen, You-Tang et al. (2010) Molecular mechanisms mediating preconditioning following chronic ischemia differ from those in classical second window. Am J Physiol Heart Circ Physiol 299:H752-62
Ho, David; Yan, Lin; Iwatsubo, Kousaku et al. (2010) Modulation of beta-adrenergic receptor signaling in heart failure and longevity: targeting adenylyl cyclase type 5. Heart Fail Rev 15:495-512
Shen, Weiqun; Vatner, Dorothy E; Vatner, Stephen F et al. (2010) Progressive loss of creatine maintains a near normal DeltaG approximately (ATP) in transgenic mouse hearts with cardiomyopathy caused by overexpressing Gsalpha. J Mol Cell Cardiol 48:591-9
Vatner, Stephen F; Yan, Lin; Ishikawa, Yoshihiro et al. (2009) Adenylyl cyclase type 5 disruption prolongs longevity and protects the heart against stress. Circ J 73:195-200
Hu, Che-Lin; Chandra, Rachna; Ge, Hui et al. (2009) Adenylyl cyclase type 5 protein expression during cardiac development and stress. Am J Physiol Heart Circ Physiol 297:H1776-82
Wu, Changgong; Yan, Lin; Depre, Christophe et al. (2009) Cytochrome c oxidase III as a mechanism for apoptosis in heart failure following myocardial infarction. Am J Physiol Cell Physiol 297:C928-34
Park, Misun; Shen, You-Tang; Gaussin, Vinciane et al. (2009) Apoptosis predominates in nonmyocytes in heart failure. Am J Physiol Heart Circ Physiol 297:H785-91

Showing the most recent 10 out of 71 publications