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Inflammation has been implicated in the initiation, progression and manifestation of hypertensive heart disease. We sought to determine the role of monocytes/macrophages in hypertension and pressure overload induced left ventricular (LV) remodeling.We used two models of LV hypertrophy (LVH). First, to induce hypertension and LVH, we fed Sabra salt-sensitive rats with a high-salt diet. The number of macrophages increased in the hypertensive hearts, peaking at 10 weeks after a high-salt diet. Surprisingly, macrophage depletion, by IV clodronate (CL) liposomes, inhibited the development of hypertension. Moreover, macrophage depletion reduced LVH by 17% (p0.05), and reduced cardiac fibrosis by 75%, compared with controls (p=0.001). Second, to determine the role of macrophages in the development and progression of LVH, independent of high-salt diet, we depleted macrophages in mice subjected to transverse aortic constriction and pressure overload. Significantly, macrophage depletion, for 3 weeks, attenuated LVH: a 12% decrease in diastolic and 20% in systolic wall thickness (p0.05), and a 13% in LV mass (p=0.04), compared with controls. Additionally, macrophage depletion reduced cardiac fibrosis by 80% (p=0.006). Finally, macrophage depletion down-regulated the expression of genes associated with cardiac remodeling and fibrosis: transforming growth factor beta-1 (by 80%) collagen type III alpha-1 (by 71%) and atrial natriuretic factor (by 86%).Macrophages mediate the development of hypertension, LVH, adverse cardiac remodeling, and fibrosis. Macrophages, therefore, should be considered as a therapeutic target to reduce the adverse consequences of hypertensive heart disease.

Background Human mesenchymal stromal cells ( hMSC s) from adipose cardiac tissue have attracted considerable interest in regard to cell‐based therapies. We aimed to test the hypothesis that hMSC s from the heart and epicardial fat would be better cells for infarct repair. Methods and Results We isolated and grew hMSC s from patients with ischemic heart disease from 4 locations: epicardial fat, pericardial fat, subcutaneous fat, and the right atrium. Significantly, hMSC s from the right atrium and epicardial fat secreted the highest amounts of trophic and inflammatory cytokines, while hMSC s from pericardial and subcutaneous fat secreted the lowest. Relative expression of inflammation‐ and fibrosis‐related genes was considerably higher in hMSC s from the right atrium and epicardial fat than in subcutaneous fat hMSC s. To determine the functional effects of hMSC s, we allocated rats to hMSC transplantation 7 days after myocardial infarction. Atrial hMSC s induced greatest infarct vascularization as well as highest inflammation score 27 days after transplantation. Surprisingly, cardiac dysfunction was worst after transplantation of hMSC s from atrium and epicardial fat and minimal after transplantation of hMSC s from subcutaneous fat. These findings were confirmed by using hMSC transplantation in immunocompromised mice after myocardial infarction. Notably, there was a correlation between tumor necrosis factor‐α secretion from hMSC s and posttransplantation left ventricular remodeling and dysfunction. Conclusions Because of their proinflammatory properties, hMSC s from the right atrium and epicardial fat of cardiac patients could impair heart function after myocardial infarction. Our findings might be relevant to autologous mesenchymal stromal cell therapy and development and progression of ischemic heart disease.

Genome-wide simultaneous measurements of pre-mRNA and mRNA expression reveal unexpected time-dependent transcript production and degradation profiles in response to external stimulus, as well as a striking lack of concordance between mRNA abundance and transcript production profiles., By analyzing the signals from intronic probes of exon arrays, we performed, for the first time, genome-wide measurement of pre-mRNA expression dynamics. We discovered a striking lack of correspondence between mRNA and pre-mRNA temporal expression profiles following stimulus, demonstrating that measurement of mRNA dynamics does not suffice to infer transcript production profiles. By combining simultaneous measurement of pre-mRNA and mRNA profiles with a simple new quantitative theoretical description of transcription, we are able to infer complex time dependence of both transcript production and mRNA degradation. The production profiles of many transcripts reveal an operational strategy we termed Production Overshoot, which is used to accelerate mRNA response. The biological relevance of our findings was substantiated by observing similar results when studying the response of three different mammalian cell types to different stimuli., Transcriptional responses to extracellular stimuli involve tuning the rates of transcript production and degradation. Here, we show that the time-dependent profiles of these rates can be inferred from simultaneous measurements of precursor mRNA (pre-mRNA) and mature mRNA profiles. Transcriptome-wide measurements demonstrate that genes with similar mRNA profiles often exhibit marked differences in the amplitude and onset of their production rate. The latter is characterized by a large dynamic range, with a group of genes exhibiting an unexpectedly strong transient production overshoot, thereby accelerating their induction and, when combined with time-dependent degradation, shaping transient responses with precise timing and amplitude.