Chronic pressure overload and atherosclerosis are primary etiologic factors for cardiac hypertrophy and failure. However, mechanisms underlying the transition from hypertrophy to heart failure are incompletely understood. We analyzed the development of heart failure in mice with chronic pressure overload induced by aortic constriction and compared the results with aged apolipoprotein E-deficient mice suffering from advanced atherosclerosis. We combined cardiac function analysis by echocardiography and invasive hemodynamics with a comprehensive microarray gene expression study (GSE25765-8). The microarray data showed that the onset of heart failure induced by pressure overload or advanced atherosclerosis was accompanied by a strong up-regulation of key lipid metabolizing enzymes involved in fat synthesis, storage and oxidation. Cardiac lipid overload may be involved in the progression of heart failure by enhancing cardiomyocyte death. Up-regulation of the cardiac lipid metabolism was related to oxygen and ATP depletion of failing hearts because anti-ischemic treatment with ranolazine normalized the cardiac lipid metabolism and improved cardiac function. Vice versa, inhibition of cellular respiration and ATP generation by mild thiol-blocking with cystamine triggered the cardiac lipid metabolism and caused signs of heart failure. Cardiac tissue specimens of patients with heart failure also showed high protein levels of key fat metabolizing enzymes as well as lipid accumulation. Taken together, our data strongly indicate that up-regulation of the cardiac lipid metabolism and myocardial lipid overload are underlying the development of heart failure.

Many experimental and clinical studies suggest a relationship between enhanced angiotensin II release by the angiotensinconverting enzyme (ACE) and the pathophysiology of atherosclerosis. The atherosclerosis-enhancing effects of angiotensin II are complex and incompletely understood. To identify antiatherogenic target genes, we performed microarray gene expression profiling of the aorta during atherosclerosis prevention with the ACE inhibitor, captopril. Atherosclerosis-prone apolipoprotein E (apoE)-deficient mice were used as a model to decipher susceptible genes regulated during atherosclerosis prevention with captopril. Microarray gene expression profiling and immunohistology revealed that captopril treatment for 7 months strongly decreased the recruitment of pro-atherogenic immune cells into the aorta. Captopril-mediated inhibition of plaque-infiltrating immune cells involved down-regulation of the C-C chemokine receptor 9 (CCR9). Reduced cell migration correlated with decreased numbers of aorta-resident cells expressing the CCR9-specific chemoattractant factor, chemokine ligand 25 (CCL25). The CCL25-CCR9 axis was pro-atherogenic, because inhibition of CCR9 by RNA interference in hematopoietic progenitors of apoE-deficient mice significantly retarded the development of atherosclerosis. Analysis of coronary artery biopsy specimens of patients with coronary artery atherosclerosis undergoing bypass surgery also showed strong infiltrates of CCR9-positive cells in atherosclerotic lesions. Thus, the C-C chemokine receptor, CCR9, exerts a significant role in atherosclerosis.Several clinical studies show that pharmacological inhibition of the renin-angiotensin-aldosterone system could mediate atheroprotection (1-4). In agreement with those clinical data, experimental studies demonstrated a causal relationship between angiotensin II release by the angiotensin-converting enzyme (ACE), 2 the angiotensin II AT 1 receptor, and the development of atherosclerosis because genetic inactivation of either ACE or the AT 1 receptor prevents atherosclerosis development in various animal models of atherosclerosis (5, 6). Likewise, inhibition of angiotensin II activity by ACE inhibitors or AT 1 receptor antagonists is curative in such animal models of atherosclerosis (7,8).In view of the major anti-atherosclerotic effects of ACE inhibitors and AT 1 antagonists, many studies investigated mechanisms that could contribute to atheroprotection upon angiotensin II inhibition. The effects of angiotensin II in atherosclerosis are complex involving actions on circulating blood cells and arterial smooth muscle cells as major targets (9 -11). Established pro-atherogenic effects of angiotensin II on smooth muscle cells are related to a phenotype transformation from contractile to synthetic (11). The effects of angiotensin II on circulating immune cells are less clear, although, gene inactivation studies clearly demonstrated the involvement of circulating blood and progenitor cells in the atherosclerosis-enhancing activity of ACE and the AT 1 r...

Background: Acute coronary syndrome (ACS) is a major cause of death all over the world. STEMI represents a type of myocardial infarction with acute ST elevation. We aimed to assess the predictive power of potential RNA panel expression in acute coronary syndrome. Method: We used in silico data analysis to retrieve RNAs related to glycerophospholipid metabolism dysregulation and specific to ACS that results in the selection of Alpha/Beta hydrolase fold domain4 (ABHD4) mRNA and its epigenetic regulators (Foxf1 adjacent noncoding developmental regulatory RNA (FENDRR) lncRNA, miRNA-221, and miRNA-197). We assessed the expression of the serum RNA panel in 68 patients with ACS, 21 patients with chest pain due to non-cardiac causes, and 21 healthy volunteers by quantitative real-time polymerase chain reaction. Results: The study data showed significant down regulation in the expression of the serum levels of FENDRR lncRNA and miRNA-221-3p by 120-fold and 22-fold in Unstable angina (UA) in comparison with healthy volunteers, and by 8.6-fold and 2-fold in ST segment elevation myocardial infarction (STEMI) patients versus UA; concomitant upregulation in the expression of ABHD4 mRNA and miRNA-197-5p by 444-fold and 10-fold in UA compared with healthy volunteers, and by 1.54-fold and 4.5-fold in STEMI versus unstable angina. Performance characteristics analysis showed that the ABHD4-regulating RNA panel were potential biomarkers for prediction of ACS. Moreover, there was a significant association between the 2 miRNAs and ABHD4 mRNA and the regulating FENDRR lncRNA. Conclusion: Collectively, ABHD4 mRNA regulating RNA panel based on putative interactions seems to be novel non-invasive biomarkers that could detect ACS early and stratify severity of the condition that could improve health outcome.

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