Background Inappropriately sustained inflammation is a hallmark of chronic ischemic heart failure (HF); however, the pathophysiological role of T-lymphocytes is unclear. Methods and Results Permanent coronary ligation was performed in adult C57BL/6 mice. As compared with sham-operated mice, mice with HF (8 w after ligation) exhibited the following features: 1) significant (p<0.05) expansion of circulating CD3+CD8+ cytotoxic and CD3+CD4+ helper (Th) T-lymphocytes, together with increased Th1, Th2, Th17, and regulatory T-cell (Treg) CD4+ subsets; 2) significant expansion of CD8+ and CD4+ T-cells in failing myocardium, with increased Th1, Th2, Th17, and Treg CD4+ subsets, marked reduction of the Th1/Th2 ratio, augmentation of the Th17/Treg ratio, and upregulation of Th2 cytokines; and 3) significantly increased Th1, Th2, Th17 cells, and Tregs, in the spleen and mediastinal lymph nodes, with increased expansion of splenic antigen-experienced effector and memory CD4+ T cells. Antibody-mediated CD4+ T-cell depletion in HF mice (starting 4 w after ligation) reduced cardiac infiltration of CD4+ T-cells and prevented progressive LV dilatation and hypertrophy whereas adoptive transfer of splenic CD4+ T-cells (and, to a lesser extent, cardiac CD3+ T-cells) from donor mice with HF induced long-term LV dysfunction, fibrosis, and hypertrophy in naïve recipient mice. Conclusions CD4+ T-lymphocytes are globally expanded and activated in chronic ischemic HF, with Th2 (vs Th1) and Th17 (vs Treg) predominance in failing hearts, and with expansion of memory T-cells in the spleen. Cardiac and splenic T-cells in HF are primed to induce cardiac injury and remodeling, and retain this memory upon adoptive transfer.

From ancient times, chemopreventive agents have been used to treat/prevent several diseases, including cancer. They are found to elicit a spectrum of potent responses including anti-inflammatory, anti-oxidant, anti-proliferative, anti-carcinogenic, and anti-angiogenic activity in various cell culture and some animal studies. Research over the past four decades has shown that chemopreventives affect a number of proteins involved in various molecular pathways that regulate inflammatory and carcinogenic responses in a cell. Various enzymes, transcription factors, receptors, and adhesion proteins are also affected by chemopreventives. Although, these natural compounds have shown significant efficacy in cell-culture studies, they elicited limited efficacy in various clinical studies. Their introduction into the clinical setting is hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Therefore, to circumvent these limitations and to ease their transition to clinics, alternate strategies should be explored. Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been demonstrated to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation. In this review article, we have attempted to provide a comprehensive outlook for these delivery approaches, using curcumin as a model agent, and discussed future strategies to enable the introduction of these highly potent chemopreventives into a physician’s armamentarium.

Background. Heart failure (HF) is a state of inappropriately sustained inflammation, suggesting the loss of normal immunosuppressive mechanisms. Regulatory T-lymphocytes (Tregs) are considered key suppressors of immune responses; however, their role in HF is unknown. We hypothesized that Tregs are dysfunctional in ischemic cardiomyopathy and HF, and promote immune activation and left ventricular (LV) remodeling. Methods. Adult male wild-type (WT) C57BL/6 mice, Foxp3-diptheria toxin receptor(DTR) transgenic mice, and tumor necrosis factor(TNF)α receptor-1(TNFR1)−/− mice underwent non-reperfused myocardial infarction (MI) to induce HF, or sham operation. LV remodeling was assessed by echocardiography, and histological and molecular phenotyping. Alterations in Treg profile and function were examined by flow cytometry, immunostaining, and in vitro cell assays. Results. As compared with WT sham mice, CD4+Foxp3+ Tregs in WT HF mice robustly expanded in the heart, circulation, spleen, and lymph nodes in a phasic manner after MI, beyond the early phase of wound healing, and exhibited pro-inflammatory Th1-type features with interferon-γ, TNFα, and TNFR1 expression, loss of immunomodulatory capacity, heightened proliferation, and potentiated anti-angiogenic and pro-fibrotic properties. Selective Treg ablation in Foxp3-DTR mice with ischemic cardiomyopathy reversed LV remodeling and dysfunction, alleviating hypertrophy and fibrosis, while suppressing circulating CD4+ T-cells and systemic inflammation, and enhancing tissue neovascularization. Importantly, Tregs reconstituted after ablation exhibited restoration of immunosuppressive capacity and normalized TNFR1 expression. Treg dysfunction was also tightly coupled to Treg-endothelial cell contact- and TNFR1-dependent inhibition of angiogenesis, and the mobilization and tissue infiltration of CD34+Flk1+ circulating angiogenic cells in a CCL5/CCR5-dependent manner. Anti-CD25-mediated Treg depletion in WT mice imparted similar benefits on LV remodeling, CACs, and tissue neovascularization. Conclusions. Pro-inflammatory and anti-angiogenic Tregs play an essential pathogenetic role in chronic ischemic HF to promote immune activation and pathological LV remodeling. The restoration of normal Treg function may be a viable approach to therapeutic immunomodulation in this disease.

Ingle KA, Kain V, Goel M, Prabhu SD, Young ME, Halade GV. Cardiomyocyte-specific Bmal1 deletion in mice triggers diastolic dysfunction, extracellular matrix response, and impaired resolution of inflammation. Am J Physiol Heart Circ Physiol 309: H1827-H1836, 2015. First published October 2, 2015; doi:10.1152/ajpheart.00608.2015.-The mammalian circadian clock consists of multiple transcriptional regulators that coordinate biological processes in a time-of-day-dependent manner. Cardiomyocyte-specific deletion of the circadian clock component, Bmal1 (aryl hydrocarbon receptor nuclear translocator-like protein 1), leads to age-dependent dilated cardiomyopathy and decreased lifespan in mice. We investigated whether cardiomyocytespecific Bmal1 knockout (CBK) mice display early alterations in cardiac diastolic function, extracellular matrix (ECM) remodeling, and inflammation modulators by investigating CBK mice and littermate controls at 8 and 28 wk of age (i.e., prior to overt systolic dysfunction). Left ventricles of CBK mice exhibited (P Ͻ 0.05): 1) progressive abnormal diastolic septal annular wall motion and reduced pulmonary venous flow only at 28 wk of age; 2) progressive worsening of fibrosis in the interstitial and endocardial regions from 8 to 28 wk of age; 3) increased (Ͼ1.5 fold) expression of collagen I and III, as well as the matrix metalloproteinases MMP-9, MMP-13, and MMP-14 at 28 wk of age; 4) increased transcript levels of neutrophil chemotaxis and leukocyte migration genes (Ccl2, Ccl8, Cxcl2, Cxcl1, Cxcr2, Il1␤) with no change in Il-10 and Il-13 genes expression; and 5) decreased levels of 5-LOX, HO-1 and COX-2, enzymes indicating impaired resolution of inflammation. In conclusion, genetic disruption of the cardiomyocyte circadian clock results in diastolic dysfunction, adverse ECM remodeling, and proinflammatory gene expression profiles in the mouse heart, indicating signs of early cardiac aging in CBK mice.aging; Bmal1; circadian clock; extracellular matrix; inflammation; diastolic dysfunction NEW & NOTEWORTHYCardiomyocyte-specific Bmal1 gene deletion in heart progresses to 1) diastolic dysfunction with significant age-dependent hypertrophy; 2) dilative hypertrophy marked with endocardial fibrosis and interstitial fibrosis in an age-dependent manner; and 3) age-dependent ventricular fibrosis displaying aggravated extracellular matrix deposition and defective resolution of the inflammation response.THE CIRCADIAN CLOCK is a timekeeping system that regulates physiological performance and behavior relative to day-night cycles. Oscillations in cardiovascular functions are firmly established, including time-of-day-dependent fluctuations in blood pressure, heart rate, and cardiac output (9, 10, 31). Night shift work and frequent time zone changes result in a dissociation between this intrinsic timekeeping mechanism and the environment, which is associated with increased risk of adverse cardiovascular effects (such as myocardial infarction and sudden cardiac death) (5, 15, 33). In mammals, the timekeeping ...