Integrative mechanisms linking cellular aging and vascular calcification

• Grant number: 19/21083-8
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2020
• End date: February 28, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Marcel Liberman
• Grantee: Marcel Liberman
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil

Abstract

Increased human longevity potentiates Vascular Calcification (VC) complications. Epidemiological studies show that VC increases the risk of lower limb amputations (AMI) in patients with Peripheral Arterial Disease (PAD). Moreover, VC is commonly associated with factors such as aging and the presence of Diabetes Mellitus (DM). Researchers have been using Hutchinson-Gilford syndrome (HGPS) as a model of early aging to study mechanisms associated with VC. HGPS is a rare hereditary disease characterized by premature aging caused by mutations in the LMNA gene or the Zmpste24 gene that disrupt the processing of nuclear lamina, leading to Prelamin A accumulation in the arteries. Patients with this syndrome develop severe premature Arteriosclerosis characterized by calcification of Vascular Smooth Muscle Cells (VSMC). Thus, our aim is to investigate the role of Prelamin A accumulation, cellular senescence and other cellular mechanisms of aging in amputated patients with and without DM. Confirming this hypothesis, as well as imbalance of other mechanisms of aging, will help to clarify the VC pathophysiology that impacts on PAD progression and amputation. Furthermore, we will functionally evaluate this hypothesis through gene silencing assays in cell culture using the collected samples and in an animal model of HGPS (C57BL/6-Tg (LMNA*G608G) HClns/J). We expect that VC occurs mainly in topographic regions of the vascular wall with greater Prelamin A accumulation, cellular senescence and decreased enzyme activity involving Prelamin A farnesilation. We will also assess such parameters in diabetic samples to compare with non-diabetic patients with PAD. Our results may unveil relevant therapeutic targets that may be able to interrupt and/or decrease VC progression and thus decrease complications of PAD such as mortality, AMI and loss of quality of life in these patients. (AU)