VEGF-B gene transfer resulted in prevention of the angiotensin II-induced diastolic dysfunction associated with induction of the Akt pathway, increased proliferation and number of c-kit(+) cells, as well as an increase in the capillary area in the left ventricle. VEGF-B may offer novel therapeutic possibilities for the prevention of the transition from compensated to decompensated cardiac hypertrophy and thereby for the treatment of heart failure.

The members of lethal-7 (Let-7) microRNA (miRNA) family are involved in regulation of cell differentiation and reprogramming of somatic cells into induced pluripotent stem cells. However, their function in the heart is not known. In this study, we examined the effect of inhibiting the function of Let-7c miRNA on the progression of postinfarction left ventricular (LV) remodeling in mice. Myocardial infarction was induced with permanent ligation of left anterior descending coronary artery with a 4-week follow-up period. Let-7c miRNA was inhibited with a specific antagomir administered intravenously. The inhibition of Let-7c miRNA downregulated the levels of mature Let-7c miRNA and its other closely related members of Let-7 family in the heart and resulted in increased expression of pluripotency-associated genes Oct4 and Sox2 in cardiac fibroblasts in vitro and in adult mouse heart in vivo. Importantly, Let-7c inhibitor prevented the deterioration of cardiac function postinfarction, as demonstrated by preserved LV ejection fraction and elevated cardiac output. Improvement in cardiac function by Let-7c inhibitor postinfarction was associated with decreased apoptosis, reduced fibrosis, and reduction in the number of discoidin domain receptor 2–positive fibroblasts, while the number of c-kit+ cardiac stem cells and Ki-67+ proliferating cells remained unaltered. In conclusion, inhibition of Let-7 miRNA may be beneficial for the prevention of postinfarction LV remodeling and progression of heart failure.

Introduction Th e activation of the renin-angiotensin-aldosterone system and sympathetic hyperactivation play central roles in pathogenesis of postinfarction left ventricular (LV) remodeling and heart failure. Th is understanding has provided strong therapeutic rationale for using angiotensin converting enzyme (ACE) inhibitors and beta-blockers in patients with myocardial infarction (MI). 1,2 However, data supporting the use of angiotensin receptor blockers (ARBs) for the primary prevention of myocardial infarction are generally weak and, in some cases, negative. 3-5 In the VALUE trial in hypertensive patients, the ARB valsartan-based regimen had a signifi cantly higher (19%, p < 0.02) incidence of myocardial infarction than the calcium channel blocker amlodipine-based regimen. 6 In the recently published ONTARGET trial in patients with vascular disease or high-risk diabetes, myocardial infarction occurred in 440 patients (5.2%) in the ARB telmisartan group and in 413 patients (4.8%) in the ACE inhibitor ramipril group (relative risk, 1.07, 0.94-1.22), telmisartan being equivalent to ramipril for the prespecified primary outcome of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. 7 As compared with a beta-blocker in the LIFE study, myocardial infarction occurred in 198 ARB losartan-treated and 188 beta-blocker atenolol-treated hypertensive patients (relative risk, 1.07, 0.88-1.31), while the stroke outcome was highly in favor of losartan, showing a 24.9% relative risk reduction compared with atenolol. 8 In view that the randomized, controlled trials have convincingly demonstrated that beta-blockers reduce rates of myocardial infarction and improve LV structure and function aft er MI, 1,2,5 we evaluated the eff ects of a beta-blocker, metoprolol, and an ARB, losartan, on the progression of LV remodeling and function in rats subjected to MI by ligating the left anterior descending artery (LAD). Since these experiments revealed that early treatment with metoprolol improved and losartan worsened LV systolic function, we tested the hypothesis that metoprolol and losartan may divergently aff ect apoptosis, proliferation, fi brosis, angiogenesis, or the number of cardiac stem cells (CSCs) in the LV aft er MI. Our results demonstrate that the impairment of cardiac function and structure with the ARB was associated with increased apoptosis and fi brosis whereas beta-blocker treatment attenuated adverse LV remodeling via c-kit + cells and cellular proliferation. Methods Myocardial infarction, drug treatments with osmotic minipumps and echocardiography MI was produced by ligation of the LAD. 9 Beta-blocker metoprolol (1.5 mg/kg/h) or angiotensin II type 1 (AT 1) receptor antagonist losartan (400 μg/kg/h) was administered via osmotic minipumps. Transthoracic echocardiography was performed 1 day, 2 weeks or 4 weeks aft er operation using Acuson Ultrasound System (Sequoia TM 512) and a 15-MHz linear transducer (15L8) (Acuson, Mountain View, CA). A group of rats was sacrifi...

Identification of the adult cardiac stem cells (CSCs) has offered new therapeutic possibilities for treating ischemic myocardium. CSCs positive for the cell surface antigen c-Kit are known as the primary source for cardiac regeneration. Accumulating evidence shows that chemokines play important roles in stem cell homing. Here we investigated molecular targets to be utilized in modulating the mobility of endogenous CSCs. In a four week follow-up after experimental acute myocardial infarction (AMI) with ligation of the left anterior descending (LAD) coronary artery of Sprague-Dawley rats c-Kit+ CSCs redistributed in the heart. The number of c-Kit+ CSCs in the atrial c-Kit niche was diminished, whereas increased amount was observed in the left ventricle and apex. This was associated with increased expression of stromal cell-derived factor 1 alpha (SDF1α), and a significant positive correlation was found between c-Kit+ CSCs and SDF1α expression in the heart. Moreover, the migratory capacity of isolated c-Kit+ CSCs was induced by SDF1 treatment in vitro. We conclude that upregulation of SDF1α after AMI associates with increased expression of endogenous c-Kit+ CSCs in the injury area, and show induced migration of c-Kit+ cells by SDF1.