Age-related diastolic dysfunction occurs in the absence of disease in men and mice, limiting maximum oxygen consumption and increasing congestive heart failure risk. The pathogenesis of age-related diastolic dysfunction is unknown, but two hypotheses have emerged: (1) Age-related Arterial Stiffening (AS) increases cardiac work, stimulating hypertrophy which results in diastolic dysfunction; (2) Progressive myocyte death (apoptosis and/or necrosis) stimulates hypertrophy in the remaining myocytes. We will address the roles of these two processes in the genesis of age-related diastolic dysfunction in control and transgenic mice. Age-related AS and diastolic dysfunction occur in the 30 month B6D2 mouse. Our data suggest a role for arterial smooth muscle tone rather than structural proteins changes including glucose-mediated cross-linking.
Our specific aims are: (1) to measure effects of genetically modifying individual components of AS (vascular tone and structural proteins) with age in the mouse on the development of diastolic dysfunction using, a) smooth muscle a-actin null mice (little vascular smooth muscle tone), b) Glucose Transporter (Glut 4) overexpressor (low serum glucose), c) matrix gla +1- (accelerated vascular calcification); (2) to measure effects of inhibiting myocyte death on the development of diastolic dysfunction with a) cardiac-specific Bcl-2 overexpressor (decreased apoptosis), and b) HSP-70 overexpressor (increased resistance to ischemia). We will perform serial non-invasive studies over the mouse lifespan measuring AS and cardiac function in situ, invasive studies of AS (and aortic impedance) and cardiac function, and terminal studies of apoptosis, myocyte size and function, calcium uptake and gene and protein expression for the """"""""aging phenotype."""""""" An elucidation of the genesis of age-associated diastolic dysfunction will be accomplished by information provided by the individual models. With this knowledge, preventative approaches can then be developed for the normal mouse and human.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017899-03
Application #
6616067
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Dutta, Chhanda
Project Start
2001-09-30
Project End
2006-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
3
Fiscal Year
2003
Total Cost
$376,250
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Reddy, Anilkumar K; Hartley, Craig J; Pham, Thuy T et al. (2014) Young little mice express a premature cardiovascular aging phenotype. J Gerontol A Biol Sci Med Sci 69:152-9
Hartley, Craig J; Reddy, Anilkumar K; Madala, Sridhar et al. (2010) Feasibility of dual Doppler velocity measurements to estimate volume pulsations of an arterial segment. Ultrasound Med Biol 36:1169-75
Chintalgattu, Vishnu; Ai, Di; Langley, Robert R et al. (2010) Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress. J Clin Invest 120:472-84
Reddy, Anilkumar K; Namiranian, Khodidad; Lloyd, Eric E et al. (2009) Effect of isoflurane on aortic impedance in mice. Conf Proc IEEE Eng Med Biol Soc 2009:1104-5
Reddy, Anilkumar K; Madala, Sridhar; Jones, Alan D et al. (2009) Multichannel pulsed Doppler signal processing for vascular measurements in mice. Ultrasound Med Biol 35:2042-54
Hartley, Craig J; Reddy, Anilkumar K; Michael, Lloyd H et al. (2009) Coronary flow reserve as an index of cardiac function in mice with cardiovascular abnormalities. Conf Proc IEEE Eng Med Biol Soc 2009:1094-7
Hartley, Craig J; Reddy, Anilkumar K; Madala, Sridhar et al. (2008) Doppler estimation of reduced coronary flow reserve in mice with pressure overload cardiac hypertrophy. Ultrasound Med Biol 34:892-901
Reddy, Anilkumar K; Taffet, George E; Hartley, Craig J (2008) Aortic impedance in Little mice. Conf Proc IEEE Eng Med Biol Soc 2008:1397-8
Hartley, Craig J; Reddy, Anilkumar K; Taffet, George E (2008) In-vitro evaluation of sensors and amplifiers to measure left ventricular pressure in mice. Conf Proc IEEE Eng Med Biol Soc 2008:965-8
Hartley, Craig J; Reddy, Anilkumar K; Madala, Sridhar et al. (2007) Effects of isoflurane on coronary blood flow velocity in young, old and ApoE(-/-) mice measured by Doppler ultrasound. Ultrasound Med Biol 33:512-21

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