Vascular proliferative disorders, such as atherosclerosis and restenosis, are the most common causes of severe cardiovascular diseases, but a common molecular mechanism remains elusive. Here, we identify and characterize a novel hyperplasia suppressor gene, named HSG (later re-named rat mitofusin-2). HSG expression was markedly reduced in hyper-proliferative vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rat arteries, balloon-injured Wistar Kyoto rat arteries, or ApoE-knockout mouse atherosclerotic arteries. Overexpression of HSG overtly suppressed serum-evoked VSMC proliferation in culture, and blocked balloon injury induced neointimal VSMC proliferation and restenosis in rat carotid arteries. The HSG anti-proliferative effect was mediated by inhibition of ERK/MAPK signalling and subsequent cell-cycle arrest. Deletion of the p21(ras) signature motif, but not the mitochondrial targeting domain, abolished HSG-induced growth arrest, indicating that rHSG-induced anti-proliferation was independent of mitochondrial fusion. Thus, rHSG functions as a cell proliferation suppressor, whereas dysregulation of rHSG results in proliferative disorders.

Background: It has been reported that the triglyceride-glucose (TyG) index may serve as a simple and credible surrogate marker of insulin resistance (IR). However, its association with macrovascular and microvascular damage is unclear. Accordingly, the objective of the present study is to investigate the association of macrovascular and microvascular damage with the TyG index. Methods: A total of 2830 elderly participants from the Northern Shanghai Study (NSS) were enrolled. The TyG index was calculated as ln[fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Parameters of vascular damage, including carotid-femoral pulse wave velocity (cf-PWV), brachial-ankle pulse wave velocity (ba-PWV), ankle-brachial index (ABI), carotid intima-media thickness (CMT), carotid plaque, estimated glomerular filtration rate (eGFR) and the urine albumin-to-creatinine ratio (UACR), were measured and calculated. Results: In univariate logistic regression, an increased TyG index was associated with a higher risk of cf-PWV > 10 m/s, ba-PWV > 1800 cm/s, ABI < 0.9, microalbuminuria (MAU) and chronic kidney disease (CKD). In multivariable logistic regression, there was a significant increase in the risk of cf-PWV > 10 m/s (OR = 1.86, 95% confidence interval [95% CI] 1.37-2.53, P for trend < 0.001), ba-PWV > 1800 cm/s (OR = 1.39, [95% CI] 1.05-1.84, P for trend = 0.02), MAU (OR = 1.61, [95% CI] 1.22-2.13, P for trend < 0.001) and CKD (OR = 1.67, [95% CI] 1.10-1.50, P for trend = 0.02) after adjustment for age, sex, BMI, waist circumference, smoking habit, hypertension, family history of premature CVD, diabetes, HDL-C, LDL-C, insulin therapy and statin therapy. However, no significant relationship was observed between the TyG index and lower extremity atherosclerosis, carotid hypertrophy or carotid plaque. Conclusion: An elevated TyG index was significantly associated with a higher risk of arterial stiffness and nephric microvascular damage. This conclusion lends support to the clinical significance of the TyG index for the assessment of vascular damage.

No abstract

Abstract-Previous studies have shown that mitofusin 2 (Mfn-2) (or hyperplasia suppressor gene [HSG]) inhibits vascular smooth muscle cell (VSMC) proliferation. Here, we demonstrate that Mfn-2 is a primary determinant of VSMC apoptosis. First, oxidative stress with H 2 O 2 , inhibition of protein kinase C with staurosporine, activation of protein kinase A with forskolin, and serum deprivation concurrently elevate Mfn-2 expression and induce VSMC apoptosis. Second, overexpression of Mfn-2 also triggers apoptosis of VSMCs in culture and in balloon-injured rat carotid arteries, thus contributing to Mfn-2-mediated prevention of neointima formation after angioplasty. Third, Mfn-2 silencing protects VSMCs against H 2 O 2 or Mfn-2 overexpression-induced apoptosis, indicating that upregulation of Mfn-2 is necessary and sufficient for oxidative stress-mediated VSMC apoptosis. The Mfn-2 proapoptotic effect is independent of its role in mitochondrial fusion but mainly mediated by inhibition of Akt signaling and the resultant activation of the mitochondrial apoptotic pathway, as manifested by decreased Akt phosphorylation, increased mitochondrial Bax/Bcl-2 ratio, cytochrome c release, and activation of caspases-9 and caspase-3. Furthermore, Mfn-2-induced apoptosis was blocked by overexpression of an active phosphoinositide 3-kinase mutant or Bcl-xL or inhibition of caspase-9 but not caspases-8. Key Words: PI3K-Akt Ⅲ apoptosis Ⅲ HSG Ⅲ Mfn-2 Ⅲ vascular smooth muscle cells A poptosis is a programmed cell death that is essential for embryonic development and for tissue homeostasis, remodeling, and immune responses. There are 2 major apoptotic signaling cascades: the first is the death receptor (Fas or tumor necrosis factor receptor)-mediated pathway involving activation of caspase-8 and its downstream executioner caspases; the other is the mitochondrial pathway activated by cellular deprivation or stress, and it involves sequentially the release of cytochrome c, the recruitment of apoptotic protease activating factor-1 (Apaf-1), and the activation of caspase-9 and downstream executioner caspases. [1][2][3] Defects (inhibition or exacerbation) of either pathway trigger proliferative or degenerative disorders, including atherosclerosis, restenosis, myocardial infarction, cancers, neurodegenerative diseases, and AIDS. [3][4][5][6][7] Ras, a small GTPase, plays a central role in the regulation of many fundamental biological processes, such as cell proliferation, differentiation, senescence, survival, and growth via activation of a wide array of downstream signaling pathways. Among them, the Ras-Raf-MEK-ERK/ mitogen-activated protein kinase (MAPK) pathway and the Ras-PI3K-Akt (also known as protein kinase [PK]B) pathway are vital for cell proliferation and cell survival. 8 -11 Whereas the Ras-MAPK pathway drives cell cycle progression, 9 the activation of the Ras-PI3K-Akt signaling blocks apoptotic cell death. 11 In particular, Akt-mediated phosphorylation of proapoptotic members of the Bcl-2 family, including Bad and Bax, prevents ...