Gene-Therapeutic Strategies Targeting Angiogenesis in Peripheral Artery Disease.

The World Health Organization announced that cardiovascular disease is the number one cause of death globally, representing 31% of all global deaths. Coronary artery disease (CAD) affects approximately 5% of the US population aged 40 years and older. With an age-adjusted prevalence of approximately 12%, peripheral artery disease (PAD) affects at least 8 to 12 million Americans.

Source of Chronic Inflammation in Aging.

Aging is a complex process that results from a combination of environmental, genetic, and epigenetic factors. A chronic pro-inflammatory status is a pervasive feature of aging. This chronic low-grade inflammation occurring in the absence of overt infection has been defined as "inflammaging" and represents a significant risk factor for morbidity and mortality in the elderly.

IGF Binding Protein-5 Induces Cell Senescence.

Cellular senescence is the complex process of deterioration that drives the aging of an organism, resulting in the progressive loss of organ function and eventually phenotypic aging. Senescent cells undergo irreversible growth arrest, usually by inducing telomere shortening. Alternatively, senescence may also occur prematurely in response to various stress stimuli, such as oxidative stress, DNA damage, or activated oncogenes.

Local Production of Activated Factor X in Atherosclerotic Plaque Induced Vascular Smooth Muscle Cell Senescence.

Our previous study demonstrated that coagulation factor Xa (FXa) induced endothelial cell senescence, resulting in inflammation and impaired angiogenesis. This mechanism is dictated through protease-activated receptors, PARs, insulin-like growth factor-binding protein 5 (IGFBP-5), and p53. Activation of PARs contributes to the pathophysiology of several chronic inflammatory diseases, including atherosclerosis.

Hepatocyte Growth Factor Prevented High-Fat Diet-Induced Obesity and Improved Insulin Resistance in Mice.

Obesity and its associated chronic inflammation in adipose tissue initiate insulin resistance, which is related to several pathologies including hypertension and atherosclerosis. Previous reports demonstrated that circulating hepatocyte growth factor (HGF) level was associated with obesity and type 2 diabetes. However, its precise role in obesity and related-pathology is unclear.

Activated Factor X Induces Endothelial Cell Senescence Through IGFBP-5.

Uncontrolled coagulation contributes to the pathophysiology of several chronic inflammatory diseases. In these conditions, senescent cells are often observed and is involved in the generation of inflammation. The coincidence of hyper-coagulation, cell senescence, and inflammation suggests the existence of a common underlying mechanism.

Induction of Angiogenesis by a Type III Phosphodiesterase Inhibitor, Cilostazol, Through Activation of Peroxisome Proliferator-Activated Receptor-γ and cAMP Pathways in Vascular Cells.

Objective: Peripheral arterial disease is highly prevalent in the elderly and in the subjects with cardiovascular risk factors such as diabetes. Approximately 2% to 4% of those affected with peripheral arterial disease commonly complain of intermittent claudication. Cilostazol, a type III phosphodiesterase inhibitor, is the only Food and Drug Administration-approved drug for the treatment of intermittent claudication.

Selective Blockade of Periostin Exon 17 Preserves Cardiac Performance in Acute Myocardial Infarction.

We previously reported that overexpression of full-length periostin, Pn-1, resulted in ventricular dilation with enhanced interstitial collagen deposition in a rat model. However, other reports have documented that the short-form splice variants Pn-2 (lacking exon 17) and Pn-4 (lacking exons 17 and 21) promoted cardiac repair by angiogenesis and prevented cardiac rupture after acute myocardial infarction. The apparently differing findings from those reports prompted us to use a neutralizing antibody to selectively inhibit Pn-1 by blockade of exon 17 in a rat acute myocardial infarction model.

Gene therapy in peripheral artery disease.

Introduction: Despite the remarkable progress of medicine and endovascular procedures for revascularization, patients with critical limb ischemia (CLI) remain at high risk for amputation and often have a low quality of life due to pain and ulcers in the ischemic leg. Thus, a novel strategy for generating new blood vessels in CLI patients without treatment options is vital. Pre-clinical studies and Phase I clinical trials using VEGF and fibroblast growth factor (FGF) demonstrated promising results; however, more rigorous Phase II and III clinical trials failed to demonstrate benefits for CLI patients.

Anti-inflammatory effects of hepatocyte growth factor on the vicious cycle of macrophages and adipocytes.

The paracrine loop involving inflammatory cytokines between adipocytes and macrophages establishes a vicious cycle that aggravates pro-inflammatory changes in adipose tissue. The serum level of hepatocyte growth factor (HGF) is increased in metabolic syndrome, but whether HGF is beneficial or detrimental in inflammatory conditions is unclear. We previously reported that HGF has strong anti-inflammatory effects.

Telmisartan exerts renoprotective actions via peroxisome proliferator-activated receptor-γ/hepatocyte growth factor pathway independent of angiotensin II type 1 receptor blockade.

Angiotensin (Ang) II type 1 receptor blockers have demonstrated beneficial effects beyond blood pressure control in the treatment of chronic kidney disease. There is clinical evidence that telmisartan is more effective than losartan in reducing proteinuria in hypertensive patients with diabetic nephropathy, because it is a partial agonist of peroxisome-proliferator activated receptor-γ (PPARγ), as well as an Ang II type 1 receptor blocker (AMADEO Study [A comparison of telMisartan versus losArtan in hypertensive type 2 DiabEtic patients with Overt nephropathy]). In this study, we examined the role of PPARγ activation in the renal protective actions of telmisartan using Ang II type 1 receptor-deficient mice.