Abstract TAC296: Smooth muscle cell poly (ADP-ribose) polymerase 1 contributes to the development of aging-associated arterial stiffening

Background: Cardiovascular disease (CVD) remains a leading cause of adult mortality with prevalence increasing with age. Importantly, aging-associated arterial stiffening is a strong risk factor for the development of CVD. Poly (ADP-ribose) polymerase 1 (PARP1), an enzyme involved in DNA repair, has increased activation and expression with age and may represent a novel therapeutic target in aging-associated CVD. Despite this, its role in aging-induced arterial stiffening remains unknown. We thus hypothesized that in aging, as DNA damage accumulates, PARP1 activity and expression is enhanced, contributing to excessive arterial stiffness and development of CVD. Methods: We created a novel transgenic mouse model with PARP1 deleted from smooth muscle cells (SMC). Male and female, SMC-PARP1-intact and SMC-PARP1-knockout (KO) mice were studied at young (3 months) and aged (18 months) time points. SMC-PARP1 deletion was confirmed by aortic PARP1 protein quantification. Arterial stiffness was measured via pulse wave velocity (PWV and fibrosis analyzed by histological Masson’s trichrome staining. Blood pressure (BP) was measured in vivo via radiotelemetry. Results: In male and female SMC-PARP1-intact mice, arterial stiffening increased with age ( p <.0001 vs. young male and female intact mice). The aging-associated rise in arterial stiffening was prevented in both male and female SMC-PARP1-KO mice ( p <0.0001 intact vs. KO). SMC-PARP1 deletion did not protect either male ( p <0.01 vs. young KO male mice) or females ( p <0.001 vs. young KO female mice) from aging-induced aortic fibrosis. No differences in blood pressure parameters were detected between genotypes in young or aged males or female mice. Conclusion: SMC-PARP1 deletion prevents aging-associated arterial stiffness in both sexes, independent of increases in vascular fibrosis. SMC-PARP1 deletion did not impact baseline mean arterial pressure in either sex, suggesting the role of SMC-PARP1 in aging-associated arterial stiffening is independent of alterations in blood pressure. Overall, these data support a role for SMC-PARP1 as a regulator of vascular aging. Further studies are required to determine mechanisms relating to how SMC-PARP1 contributes to aging-associated arterial stiffening.