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Although cardiac hypertrophy is widely recognized as a risk factor that leads to cardiac dysfunction and, ultimately, heart failure, the complex mechanisms underlying cardiac hypertrophy remain incompletely characterized. The nuclear receptor peroxisome proliferator‐activated receptor δ (PPARδ) is involved in the regulation of cardiac lipid metabolism. Here, we describe a novel PPARδ‐dependent molecular cascade involving microRNA‐29a (miR‐29a) and atrial natriuretic factor (ANF), which is reactivated in cardiac hypertrophy. In addition, we identify a novel role of miR‐29a, in which it has a cardioprotective function in isoproterenol hydrochloride‐induced cardiac hypertrophy by targeting PPARδ and downregulating ANF. Finally, we provide evidence that miR‐29a reduces the isoproterenol hydrochloride‐induced cardiac hypertrophy response, thereby underlining the potential clinical relevance of miR‐29a in which it may serve as a potent therapeutic target for heart hypertrophy treatment. [ABSTRACT FROM AUTHOR]

Growing genetic and epidemiological evidence suggests a direct connection between the disruption of circadian rhythm and breast cancer. Moreover, the expression of several molecular components constituting the circadian clock machinery has been found to be modulated by estrogen-estrogen receptor α (E2-ERα) signaling in ERα-positive breast cancer cells. In this study, we investigated the regulation of CLOCK expression by ERα and its roles in cell proliferation. Immunohistochemical analysis of human breast tumor samples revealed high expression of CLOCK in ERα-positive breast tumor samples. Subsequent experiments using ERα-positive human breast cancer cell lines showed that both protein and mRNA levels of CLOCK were up-regulated by E2 and ERα. In these cells, E2 promoted the binding of ERα to the EREs (estrogen-response elements) of CLOCK promoter, thereby up-regulating the transcription of CLOCK. Knockdown of CLOCK attenuated cell proliferation in ERα-positive breast cancer cells. Taken together, these results demonstrated that CLOCK could be an important gene that mediates cell proliferation in breast cancer cells. [ABSTRACT FROM AUTHOR]

Insulin is a peptide hormone produced by beta cells of the pancreas. The roles of insulin in energy metabolism have been well studied, with most of the attention focused on glucose utilization, but the roles of insulin in cell proliferation and differentiation remain unclear. In this study, we observed for the first time that 10 nmol/L insulin treatment induces cell proliferation and cardiac differentiation of P19 CL6 cells, whereas 50 and 100 nmol/L insulin treatment induces P19 CL6 cell apoptosis and blocks cardiac differentiation of P19 CL6 cells. By using real-time polymerase chain reaction ( PCR) and Western blotting analysis, we found that the m RNA levels of cyclin D1 and α myosin heavy chain (α- MHC) are induced upon 10 nmol/L insulin stimulation and inhibited upon 50/100 nmol/L insulin treatment, whereas the m RNA levels of BCL-2-antagonist of cell death ( BAD) exists a reverse trend. The similar results were observed in P19 CL6 cells expressing GATA-6 or peroxisome proliferator-activated receptor α ( PPARα). Our results identified the downstream targets of insulin, cyclin D1, BAD, α- MHC, and GATA-4, elucidate a novel molecular mechanism of insulin in promoting cell proliferation and differentiation. [ABSTRACT FROM AUTHOR]

We recently demonstrated that fenofibrate induces the activities of citrate synthase and NADH oxidase in cardiac mitochondria. To further determine the molecular mechanisms underlying fenofibrate action, 8-week-old mice were administered fenofibrate (100 mg/kg/day) for 7 and 14 days, and the expression of genes involved in cardiac mitochondrial function, such as nuclear respiratory factor 1 transcript variant 2 (NRF-1-L) and 6 (NRF-1-S), mitochondrial outer membrane protein 40 (Tom40), lipoic acid synthetase (Lias), cytochrome b, medium-chain acyl-coenzyme A dehydrogenase (MCAD) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) was determined. Expression of PGC-1α, a key regulator of the entire fatty acid oxidation system, was significantly downregulated after 14 days of fenofibrate administration. Moreover, ventricular triglycerides were also accumulated following 14 days of fenofibrate administration. Thus, fenofibrate functions to improve myocardial lipid accumulation and to prevent PGC-1α induction, which is crucial for understanding the molecular mechanisms underlying fenofibrate action on the heart.