Coronary artery disease is the leading cause of death in western countries, and its association with lower extremity peripheral artery disease (LE-PAD) represents an independent predictor of worse ...outcome. However, the molecular mechanisms underlying these effects are currently unknown.
To investigate these processes, we used in vitro approaches and several mouse models: (i) unilateral limb ischaemia by left common femoral artery ligation peripheral ischaemia (PI), n = 38; (ii) myocardial infarction by permanent ligation of the left descending coronary artery (MI, n = 40); (iii) MI after 5 weeks of limb ischaemia (PI + MI, n = 44); (iv) sham operation (SHAM, n = 20). Compared with MI, PI + MI hearts were characterized by a significant increase in cardiomyocyte apoptosis, larger infarct areas, and decreased cardiac function. By using a proteomic approach, we identified a ≅ 8 kDa circulating peptide, Dermcidin (DCD), secreted by ischaemic skeletal muscles, enhancing cardiomyocytes apoptosis under hypoxic conditions and infarct size after permanent coronary artery ligation. siRNA interference experiments to reduce DCD circulating levels significantly reduced infarct size and ameliorated cardiac function after MI.
Our data demonstrate that chronic limb ischaemia activates detrimental pathways in the ischaemic heart through humoral mechanisms of remote organ crosstalk. Thus, DCD may represent a novel important myokine modulating cardiomyocyte survival and function.
Pressure overload has been shown to induce mitogen activated protein kinases (MAPKs) and reactivate the atrial natriuretic factor in the heart. To test the sensitivity of these signals to pressure ...overload, we assayed the activity of MAPKs extracellular signal-regulated kinase, c-Jun N-terminal kinase 1, and p38 in protein lysates from the left ventricle (LV) or white blood cells (WBC) isolated from aortic banded mice with varying levels of pressure overload. In separated mice we measured atrial natriuretic factor mRNA levels by Northern blotting. As expected, a significant induction of atrial natriuretic factor mRNA levels was observed after aortic banding, and it significantly correlated with the trans-stenotic systolic pressure gradient but not with the LV weight:body weight ratio. In contrast, a significant correlation with systolic pressure gradient or LV weight:body weight ratio was observed for all of the MAPK activity detected in LV samples or WBCs. Importantly, LV activation of MAPKs significantly correlated with their activation in WBCs from the same animal. To test whether MAPK activation in WBCs might reflect uncontrolled blood pressure levels in humans, we assayed extracellular signal-regulated kinase, c-Jun N-terminal kinase 1, and p38 activation in WBCs isolated from normotensive volunteers, hypertensive patients with controlled blood pressure values, or hypertensive patients with uncontrolled blood pressure values. Interestingly, in hypertensive patients with controlled blood pressure values, LV mass and extracellular signal-regulated kinase phosphorylation were significantly reduced compared with those in hypertensive patients with uncontrolled blood pressure values. These results suggest that MAPKs are sensors of pressure overload and that extracellular signal-regulated kinase activation in WBCs might be used as a novel surrogate biomarker of uncontrolled human hypertension.
The regulation of angiogenesis, both its increase or decrease, could be an important therapeutic target for a number of diseases. The role of angiogenesis in atherosclerosis and other cardiovascular ...diseases is currently controversial. Indeed, angiogenic therapy has been widely regarded as an attractive approach to treat ischemic heart disease, but a variety of studies also suggest that neovascularization contributes to the growth of atherosclerotic lesions and is a key factor in plaque destabilization leading to rupture. Recent studies have shown that the phosphatidylinositol 3-kinase (PI3K) family of enzymes plays an important role in the regulation of tumor growth and angiogenesis. PI3Ks and their downstream effector PKB/Akt can be activated by a variety of extracellular signals and regulate a number of cellular processes including cell proliferation, survival, protein synthesis, tumor growth and angiogenesis. Several lines of evidence indicate that inhibition of PI3K suppresses angiogenesis and tumor growth. Nonselective PI3K inhibitors, wortmannin and LY294002, are commonly used to inhibit cancer cell proliferation and tumor growth, and sensitize tumor cells to the treatment with chemotherapeutic drugs and radiation. This review will dissect the role of the PI3Ks pathway in different animal models, and will describe possible future directions for the development of novel therapeutic strategies to modulate the angiogenetic process by regulating PI3K signaling.
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