Impact of aging and accumulation of prelamin A on vascular calcification in amputees

• Grant number: 19/11903-8
• Support Opportunities: Scholarships in Brazil - Doctorate
• Effective date (Start): February 01, 2021
• Effective date (End): January 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Marcel Liberman
• Grantee: Eduardo Varejão Díaz Placencia
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil

Abstract

Due to the increasing of human longevity, complications from Vascular Calcification (VC) became more evident. 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 accumulation of prelamin A in the arteries. Patients with this syndrome develop severe premature atherosclerosis characterized by calcification of Vascular Smooth Muscle Cells (VSMC). Thus, our study intends to investigate the accumulation of prelamin A, cell senescence and other aging markers in amputated patients with and without DM. Confirming this hypothesis, as well as the expression of other aging markers, will be important to clarify the VC pathophysiology that impacts on DAP and amputation. Furthermore, we will functionally evaluate the hypothesis through gene silencing assays in cell culture using the collected samples. Our expectation is that VC occurs in arterial topography with greater accumulation of prelamin A, cellular senescence and less activity of enzymes that exert farnesilation of prelamin A. We will also evaluate such parameters in diabetic samples for comparison with non-diabetic patients with PAD. Our results may reveal relevant therapeutic targets and may interrupt and/or decrease VC progression and thus avoid higher complications of PAD such as mortality, AMI and loss of quality of life of patients. (AU)