The concept of cell death has been expanded beyond apoptosis and necrosis to additional forms, including necroptosis, pyroptosis, autophagy, and ferroptosis. These cell death modalities play a critical role in all aspects of life, which are noteworthy for their diverse roles in diseases. Atherosclerosis (AS) and vascular calcification (VC) are major causes for the high morbidity and mortality of cardiovascular disease. Despite considerable advances in understanding the signaling pathways associated with AS and VC, the exact molecular basis remains obscure. In the article, we review the molecular mechanisms that mediate cell death and its implications for AS and VC. A better understanding of the mechanisms underlying cell death in AS and VC may drive the development of promising therapeutic strategies.

Background: Arterial media calcification (AMC) is highly prevalent and is a major cause of morbidity, mortality, stroke and amputation in patients with diabetes mellitus (DM). Previous research suggests that advanced glycation end products (AGEs) are responsible for vascular calcification in diabetic patients. The potential link between oxidative stress and AGEs-induced vascular calcification, however, has not been examined. Methods: Male Wistar rats received a high fat diet for 8 weeks followed by a single dose of streptozotocin to induce DM (DM). Calcification was induced with Vitamin D3 and nicotine (VDN). We started VDN treatment at 1 week after the initial streptozotocin injection (DM+VDN). Age-matched rats were used as controls (CON). Metabolic parameters, aortic calcium content, alkaline phosphatase (ALP) protein, malondialdehyde (MDA) content, Cu/Zn superoxide dismutase (SOD) activity, aorta receptor for advanced glycation end products (RAGE) and aorta AGEs levels were measured. In vitro, vascular smooth muscle cells (VSMCs) were cultured with AGEs in DMEM containing 10 mmol·L^-1 ß -glycerophosphate (ß-GP). Calcium content and ALP activity were used to identify osteoblastic differentiation and mineralization. Western blots were used to examine protein expression of Cu/Zn SOD, NADPH oxidase Nox1 and RAGE. In addition, the intracellular reactive oxygen species (ROS) generation was evaluated using fluorescent techniques with dihydroethidine (DHE) method. Results: The DM+VDN group showed a significant increase in aortic calcium content, levels of aorta AGEs, MDA content, ALP protein levels and RAGE expression, although Cu/Zn SOD activity decreased significantly. In vitro, enhanced Nox1, RAGE expression as well as the production of intracellular superoxide anions, and reduced expression of Cu/Zn SOD induced by AGEs were attenuated by the anti-RAGE antibody or a ROS inhibitor. Furthermore, the AGEs-stimulated ROS increase was also significantly inhibited by a SOD mimetic. Increased ALP activity and calcium deposition were also inhibited markedly by the ROS inhibitor and the anti-RAGE antibody. Conclusions: These results suggest that AGEs enhance vascular calcification partly through a RAGE/oxidative stress pathway.

Pyruvate dehydrogenase kinase 4 (PDK4) is an important mitochondrial matrix enzyme in cellular energy regulation. Previous studies suggested that PDK4 is increased in the calcified vessels of patients with atherosclerosis and is closely associated with mitochondrial function, but the precise regulatory mechanisms remain largely unknown. This study aims to investigate the role of PDK4 in vascular calcification and the molecular mechanisms involved. Using a variety of complementary techniques, we found impaired autophagic activity in the process of vascular smooth muscle cells (VSMCs) calcification, whereas knocking down PDK4 had the opposite effect. PDK4 drives the metabolic reprogramming of VSMCs towards a Warburg effect, and the inhibition of PDK4 abrogates VSMCs calcification. Mechanistically, PDK4 disturbs the integrity of the mitochondria-associated endoplasmic reticulum membrane, concomitantly impairing mitochondrial respiratory capacity, which contributes to a decrease in lysosomal degradation by inhibiting the V-ATPase and lactate dehydrogenase B interaction. PDK4 also inhibits the nuclear translocation of the transcription factor EB, thus inhibiting lysosomal function. These changes result in the interruption of autophagic flux, which accelerates calcium deposition in VSMCs. In addition, glycolysis serves as a metabolic adaptation to improve VSMCs oxidative stress resistance, whereas inhibition of glycolysis by 2-deoxy-D-glucose induces the apoptosis of VSMCs and increases the calcium deposition in VSMCs. Our results suggest that PDK4 plays a key role in vascular calcification through autophagy inhibition and metabolic reprogramming.

In the U.S. general population, there is a lack of understanding regarding the association between the systemic immune inflammation (SII) index and estimated pulse wave velocity (ePWV), atherogenic index of plasma (AIP), and triglyceride-glucose (TyG) index and cardiovascular disease (CVD). As a result, the objective of our research was to investigate the association between the SII index and ePWV, AIP, and TyG index and incident CVD. We used the National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2018 to conduct this study. The correlation between the SII index and ePWV, AIP, and TyG index was examined using generalized additive models with smooth functions. In addition, the association between SII index and triglyceride (TC), high-density lipoprotein cholesterol (HDL-C), and fast glucose (FBG) also were explored. Finally, we further performed multivariable logistic regression analysis, restricted cubic spline (RCS) plots, and subgroup analysis to study the connection between the SII index and CVD. Our analysis included 17389 subjects from the NHANES database. A substantial positive association existed between SII, WV, and the TyG index. In addition, with the increase of the SII index, AIP showed a trend of decreasing first, then rising, and then decreasing. The SII index was inversely and linearly associated with triglyceride (TG), while positively and linearly associated with fast glucose (FBG). However, high-density lipoprotein cholesterol (HDL-C) had a tendency of first declining, then climbing, and finally falling with the rise in the SII index. After adjusting for potential confounders, compared with the lowest quartiles, the odds ratios with 95% confidence intervals for CVD across the quartiles were 0.914 (0.777, 1.074), 0.935 (0.779, 1.096), and 1.112 (0.956, 1.293) for SII index. The RCS plot showed an inverse U-shaped curve relationship between the SII index and CVD. Overall, this study found a strong correlation between a higher SII index and ePWV and the TyG index. Additionally, these cross-sectional data also revealed a U-shaped connection between the SII index and CVD.