Biomedical subjects

Gohar Azhar

Publications and source records attributed to Gohar Azhar.

5 recordsLinked to original sources

PubMed2006

Maintaining serum response factor activity in the older heart equal to that of the young adult is associated with better cardiac response to isoproterenol stress.

To understand the effect of transcription regulation in modulating cardiac aging, we sought to study the role of serum response factor (SRF), a key transcription factor in the heart that is normally increased with senescence and also in congestive heart failure. A Tet-Off gene expression system was used for cardiac-specific over-expression of a mutant SRF protein. In these binary transgenic mice, there is no age-related increase in SRF protein expression; in fact, there appeared to be a mild reduction of SRF protein (Mild-R SRF Tg). The older, middle-aged (15 mo) Mild-R SRF Tg mice appeared healthier and were better able to maintain their left ventricular systolic pressure (LVSP) in response to moderate â-adrenergic stimulation compared with age-matched Non-Tg mice, which demonstrated a negative ionotropic response. The Mild-R SRF Tg hearts had lower mRNA expression of BNP (p < 0.05), and the sodium calcium exchanger (p < 0.05), compared to Non-Tg. Mild-R SRF Tg had higher mRNA levels of SERCA2 (p < 0.05) and ryanodine receptor 2 (p < 0.05) compared to Non-Tg hearts. These findings suggest that preventing the age-associated increase in SRF is associated with better preserved intracellular calcium handling and functional response to stress; it might be advantageous for the older adult heart. This mouse model could be helpful in elucidating the molecular mechanisms underlying certain age-related changes in cardiac reserve capacity and response to stress.

Age Factors↗

PubMed2006

Zipzap/p200 is a novel zinc finger protein contributing to cardiac gene regulation.

Serum response factor (SRF) plays an important role in the regulation of immediate-early genes and muscle-specific genes, while SRF cofactors may contribute significantly to assist in tissue-specific, development-stage related regulation of SRF-target genes. We recently cloned a novel SRF cofactor, termed zipzap/p200, which is a zinc finger protein yet to be characterized. We determined that zipzap/p200 is a 200-kDa protein with two classic C2H2 zinc fingers at the carboxyl terminus where the nucleotide sequence was highly conserved among human, mouse, and rat. The zipzap gene was expressed in multiple tissues and at multiple ages, including the fetal and adult heart. The zipzap protein interacted with SRF in vivo and was found in protein complexes containing SRF and other SRF cofactors, including p49/strap and Nkx2.5. Zipzap/p200 activated the promoter of cardiac genes and potentiated the effect of myocardin on ANF promoter activity. Therefore, zipzap may serve as a transcription co-activator for the regulation of cardiac gene expression. Our data support the notion that a number of SRF cofactors may participate in gene regulation and thereby contribute to the delicate control of gene expression in complex biological processes.

Adult↗

PubMed2006

Nutrition and cardiac cachexia.

PURPOSE OF REVIEW: Congestive heart failure is a leading cause of morbidity and mortality, especially in older persons. In advanced stages of the disease, congestive heart failure can be associated with serious complications such as cardiac cachexia (defined here as weight loss of more than 6% in 6 months). This review will discuss recent insights into the pathophysiology, anthropometric predictors and potential management of cardiac cachexia. RECENT FINDINGS: Cardiac cachexia and the associated progressive weight loss are sometimes overlooked by care providers. A delay in diagnosis often results in further loss of vital tissues, progressive weakness, fall-related injuries and potentially long-term care institutionalization and/or death. Emerging data suggest that congestive heart failure is a dynamic disorder of many organ systems, including the myocardial, neurohormonal, immune, vascular, gastrointestinal, renal and musculoskeletal systems. It is becoming more widely appreciated that it is the deterioration of this interactive multisystem complex that results in the systemic inflammation and progressive wasting and atrophy of muscle and other organ tissues, which is the hallmark of cardiac cachexia. SUMMARY: Cardiac cachexia in congestive heart failure patients may be associated with a low level of physical activity. A high systemic inflammatory state is another marker of cardiac cachexia. Prudent anti-inflammatory nutrition, dietary supplements and exercise can serve to ameliorate and/or potentially prevent progressive wasting. A better understanding of factors contributing to the development of cardiac cachexia will enable us to design preventive strategies and provide improved care for individuals with this debilitating condition.

Aged↗

PubMed2004

Identification of a novel serum response factor cofactor in cardiac gene regulation.

The transcription factor serum response factor (SRF) plays an important role in the regulation of a variety of cardiac genes during development and during adult aging. A novel SRF cofactor, herein called p49/STRAP, for SRF-dependent transcription regulation-associated protein, was recently identified in our laboratory. This protein interacted mainly with the transcriptional activation domain of the SRF protein and was found to bind to SRF or to the complex of SRF and another cofactor, such as myocardin or Nkx2.5. The expression of p49/STRAP affected the promoter activity of SRF target genes in a non-uniform manner. For example, p49 activated MLC2v and cardiac actin promoters when it was co-transfected with SRF, but it repressed atrial natriuretic factor promoter activity, which was strongly induced by myocardin. The p49/STRAP mRNA was observed to be highly expressed in fetal, adult, and senescent human hearts, and also in hearts of young adult and old mice, suggesting that p49/STRAP may be an important SRF cofactor in the transcriptional regulation of mammalian cardiac muscle genes throughout the life span.

Actins↗

PubMed2003

Model of functional cardiac aging: young adult mice with mild overexpression of serum response factor.

Serum response factor (SRF) is an important transcription factor that may have a role in the maintenance of cardiac structure and function. The level of SRF mRNA expression increases approximately 16% in the hearts of mice during adult aging. To model the effect of mild SRF elevation in the aging heart, transgenic mice with low levels of SRF overexpression were generated. By 6 mo of age, the transgenic mice had a 19% increase of heart-to-body weight ratio compared with nontransgenic mice. In addition, they had a 12% increase in myocyte size, a 6.7% increase in collagen deposition, and altered gene expression of a number of muscle-specific and cardiac genes. Doppler echocardiography revealed that these transgenic mice had increased left ventricular wall thickness and decreased left ventricular (LV) volumes, increased LV stiffness with 20% reduction in early diastolic LV filling (peak E), and 35% decline in peak E-to-peak A (late diastolic filling) ratio. The observed changes, especially those in the E/A ratio, are similar to those seen clinically in late life as a part of human adult myocardial aging.

Aging↗