Ang II, the primary effector pleiotropic hormone of the renin-angiotensin system (RAS) cascade, mediates physiological control of blood pressure and electrolyte balance through its action on vascular tone, aldosterone secretion, renal sodium absorption, water intake, sympathetic activity and vasopressin release. It affects the function of most of the organs far beyond blood pressure control including heart, blood vessels, kidney and brain, thus, causing both beneficial and deleterious effects. However, the protective axis of the RAS composed of ACE2, Ang (1-7), alamandine, and Mas and MargD receptors might oppose some harmful effects of Ang II and might promote beneficial cardiovascular effects. Newly identified RAS family peptides, Ang A and angioprotectin, further extend the complexities in understanding the cardiovascular physiopathology of RAS. Most of the diverse actions of Ang II are mediated by AT1 receptors, which couple to classical Gq/11 protein and activate multiple downstream signals, including PKC, ERK1/2, Raf, tyrosine kinases, receptor tyrosine kinases (EGFR, PDGF, insulin receptor), nuclear factor κB and reactive oxygen species (ROS). Receptor activation via G12/13 stimulates Rho-kinase, which causes vascular contraction and hypertrophy. The AT1 receptor activation also stimulates G protein-independent signaling pathways such as β-arrestin-mediated MAPK activation and Src-JAK/STAT. AT1 receptor-mediated activation of NADPH oxidase releases ROS, resulting in the activation of pro-inflammatory transcription factors and stimulation of small G proteins such as Ras, Rac and RhoA. The components of the RAS and the major Ang II-induced signaling cascades of AT1 receptors are reviewed.
The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular disorders. Pharmacologic interventions targeting the RAS cascade have led to the discovery of renin inhibitors, angiotensin-converting enzyme inhibitors, and AT(1) receptor blockers (ARBs) to treat hypertension and some cardiovascular and renal disorders. Mutagenesis and modeling studies have revealed that differential functional outcomes are the results of multiple active states conformed by the AT(1) receptor upon interaction with angiotensin II (Ang II). The binding of agonist is dependent on both extracellular and intramembrane regions of the receptor molecule, and as a consequence occupies more extensive area of the receptor than a non-peptide antagonist. Both agonist and antagonist bind to the same intramembrane regions to interfere with each other's binding to exhibit competitive, surmountable interaction. The nature of interactions with the amino acids in the receptor is different for each of the ARBs given the small differences in the molecular structure between drugs. AT(1) receptors attain different conformation states after binding various Ang II analogues, resulting in variable responses through activation of multiple signaling pathways. These include both classical and non-classical pathways mediated through growth factor receptor transactivations, and provide cross-communication between downstream signaling molecules. The structural requirements for AT(1) receptors to activate extracellular signal-regulated kinases 1 and 2 through G proteins, or G protein-independently through β-arrestin, are different. We review the structural and functional characteristics of Ang II and its analogs and antagonists, and their interaction with amino acid residues in the AT(1) receptor.
Noncommunicable diseases (NCDs) have become important causes of mortality on a global scale. According to the report of World Health Organization (WHO), NCDs killed 38 million people (out of 56 million deaths that occurred worldwide) during 2012. Cardiovascular diseases accounted for most NCD deaths (17.5 million NCD deaths), followed by cancers (8.2 million NCD deaths), respiratory diseases (4.0 million NCD deaths) and diabetes mellitus (1.5 million NCD deaths). Globally, the leading cause of death is cardiovascular diseases; their prevalence is incessantly progressing in both developed and developing nations. Diabetic patients with insulin resistance are even at a greater risk of cardiovascular disease. Obesity, high cholesterol, hypertriglyceridemia and elevated blood pressure are mainly considered as major risk factors for diabetic patients afflicted with cardiovascular disease. The present review sheds light on the global incidence of cardiovascular disease and diabetes mellitus. Additionally, measures to be taken to reduce the global encumbrance of cardiovascular disease and diabetes mellitus are highlighted.
An interactive workshop on 'The Critical Steps for Successful Research: The Research Proposal and Scientific Writing' was conducted in conjunction with the 64(th) Annual Conference of the Indian Pharmaceutical Congress-2012 at Chennai, India. In essence, research is performed to enlighten our understanding of a contemporary issue relevant to the needs of society. To accomplish this, a researcher begins search for a novel topic based on purpose, creativity, critical thinking, and logic. This leads to the fundamental pieces of the research endeavor: Question, objective, hypothesis, experimental tools to test the hypothesis, methodology, and data analysis. When correctly performed, research should produce new knowledge. The four cornerstones of good research are the well-formulated protocol or proposal that is well executed, analyzed, discussed and concluded. This recent workshop educated researchers in the critical steps involved in the development of a scientific idea to its successful execution and eventual publication.
The basic concepts of research are learned through systematic literature searches which form the basis of a research statement and research topic. Then the research question, hypothesis, aim, and objectives, as well as the experimental design, are developed. Given the context provided, the primary focus is on the importance of adequately training postgraduates and young research investigators in research methodology and project development. It is evident that there is a lack of proper training in these areas, and the rapid expansion of colleges in India exacerbates this issue. To address this, research students must receive comprehensive instruction in scientific research methodology, experimental design, statistics, scientific writing, publishing, and research ethics. Our team has been conducting workshops and symposia for more than two decades to improve the current teaching methods in these areas. Most recently, we organized a series of national and international workshops and seminars in multiple states across India to fortify the core concepts of scientific research for students and faculty members. This report highlights the key aspects of these workshops and the positive outcomes experienced by participants.