Review Article

The Light and Shadow of Senescence and Inflammation in Cardiovascular Pathology and Regenerative Medicine

Table 1

Senescence in atherosclerotic lesions.

Extrinsic vascular senescence triggers
 (i) High blood cholesterol levels[17]
 (ii) Inflammatory cytokines and growth factors
 (iii) Angiotensin II
 (iv) Hyperglycemia and associated AGEs

Intrinsic vascular senescence triggers
 (i) Telomere shortening[17]
 (ii) Activation of Ras pathway
 (iii) Mytochondrial dysfunction, mtDNA mutations, and/or release of mitochondria-specific ROS[18]

Activated (↑) and inactivated (↓) molecular pathways and functions
 (i) Involvement of several genes (e.g., Klotho) and proteins (e.g., Sirtuins, progerin, JunD, p66shc, and β-amyloid peptides)[3]
 (ii) ↑ DNA damage signaling
  (a) ↑ cyclin-dependent kinase inhibitors (p15, p16, p21, p27, and/or p53)
  (b) ↓ mediators of cell cycle progression (cyclin-dependent kinase inhibitor 2A; cyclin-dependent kinases (1, 2, 4, and 6) and cyclins (A, E, and D))
  (c) ↓ tumor suppressor RB
 (iii) ↑ nuclear factor NF-κB and CCAAT/enhancer-binding protein-β pathways[3, 21]
 (iv) ↑ SASP program, which includes the secretion of IL-6, IL-8, chemokines, and activators of macrophages and monocytes (MCP, MIP, TNF-α, TGF-β, and GM-CSF), as well as ECM proteases[3, 21]
 (v) ↑ procalcific factors (RUNX-2, alkaline phosphatase, collagen I, matrix GLA protein, and BMP-2) in SMCs[12, 22]
 (vi) Impairment of eNOS and prostacyclin pathways in senescent ECs[14, 2426]
 (vii) Association between decreased levels of CDKN1 and CDKNA2 and increased propensity to develop atherosclerosis[27, 28]
 (viii) Link between CDKN1 and CDKNB2 polymorphisms and aortic aneurism[29]
 (ix) ↑ ICAM-1, PAI-1, and IL-1α and ↓ lipid metabolism ability in ECs[3033]
 (x) ↑ SASP secretion of annexins and BMPs and ↑Ca2+ in ECs favors calcification onset[34]

AGEs: advanced glycosylation end products; SMCs: smooth muscle cells; ECs: endothelial cells.