PMID- 29938610 OWN - NLM STAT- MEDLINE DCOM- 20191121 LR - 20191121 IS - 1873-4286 (Electronic) IS - 1381-6128 (Linking) VI - 24 IP - 25 DP - 2018 TI - Coronary Microvascular and Cardiac Dysfunction Due to Homocysteine Pathometabolism; A Complex Therapeutic Design. PG - 2911-2920 LID - 10.2174/1381612824666180625125450 [doi] AB - In various metabolic diseases, both the coronary circulation and cardiac metabolism are altered. Here we summarize the effects of a condition called hyperhomocysteinemia (HHcy) - which can develop due to genetic and/or environmental causes - on the function of coronary microvessels and heart. This metabolic disease is underappreciated, yet even mild or moderate elevation of plasma concentrations of homocystein (Hcy, plasma Hcy >16 microM), a sulfur-containing amino acid produced via methionine metabolism) leads to coronary and peripheral artery and even venous vessel diseases, eliciting vasomotor dysfunction and increased thrombosis, consequently increased morbidity and mortality. Yet the underlying mechanisms have not yet been revealed. Recent studies indicated that there are common pathomechanisms, which may affect several cellular functions. With methionin diet-induced HHcy two main pathomechanisms were revealed: the dysfunction of nitric oxide (NO) pathway resulting in reduced dilator responses of arteries and arterioles, and the simultaneously increased thromboxane A2 (TXA2) activity both in vessels and platelets. These changes are likely due to an increased production of reactive oxidative species (oxidative stress) due to increased NADPH oxidase assembly, which eventually lead to inflammatory processes (indicated by increases in TNFalpha, NFkappabeta, p22phox, p67phox, and rac-1, levels) and changes in various gene expressions and morphological remodeling of vessels. Increased superoxide production and reduced availability of NO alter the regulation of mitochondrial function in the myocardium. The interactions of these pathomechanisms may explain why HHcy increases the uptake of glucose and lactate and decreases the uptake of free fatty acid by the heart. The pathological consequences of HHcy could be worsening by the simultaneous presence of other risk factors, such as hyperlipidemia, diabetes mellitus and metabolic syndrome. All in all, HHcy and associated pathometabolism lead to severe changes and dysfunctions of coronary arterial vessels and cardiac function, which may not always be apparent in clinical settings but most likely contribute to the increased prevalence of cardiovascular diseases and mortality, which however can be reduced by appropriate prevention and treatments. We believe that HHcy is an underestimated - likely due to inappropriate clinical trials - but serious disease condition because it promotes the development of atherosclerosis in large arterial vessels, vasomotor dysfunction in microvessels, hypertension and thrombosis. In this review, we will summarize previous functional findings focusing on coronary vessels and cardiac function and the underlying cellular and molecular mechanisms enabling the development of novel treatments. CI - Copyright(c) Bentham Science Publishers; For any queries, please email at epub@benthamscience.org. FAU - Koller, Akos AU - Koller A AD - Research Group of Sportgenetics and Sportgerontology, Institute of Natural Sciences, University of Physical Education, Budapest, Hungary. AD - Department of Physiology, New York Medical College, Valhalla, NY, United States. AD - Institute of Neurosurgery, Medical School, University of Pecs, Pecs, Hungary. AD - Department of Pathophysiology, Semmelweis University, Budapest, Hungary. AD - Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary. FAU - Szenasi, Annamaria AU - Szenasi A AD - Department of Pathophysiology, Semmelweis University, Budapest, Hungary. AD - Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary. FAU - Dornyei, Gabriella AU - Dornyei G AD - Department of Morphology and Physiology, Faculty of Health Sciences, Semmelweis University, Budapest, Hungary. FAU - Kovacs, Nora AU - Kovacs N AD - Klinikum Ingolstadt, Medizinische Klinik I., Ingolstadt, Germany. FAU - Lelbach, Adam AU - Lelbach A AD - Research Group of Sportgenetics and Sportgerontology, Institute of Natural Sciences, University of Physical Education, Budapest, Hungary. AD - Department of Pathophysiology, Semmelweis University, Budapest, Hungary. AD - Rose Private Hospital, Budapest, Hungary. FAU - Kovacs, Imre AU - Kovacs I AD - Department of Internal Medicine/Cardiology, Sopron Health Center, Sopron, Hungary. LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review PL - United Arab Emirates TA - Curr Pharm Des JT - Current pharmaceutical design JID - 9602487 RN - 0 (Neuroprotective Agents) RN - 0LVT1QZ0BA (Homocysteine) SB - IM MH - Animals MH - Cardiovascular Diseases/drug therapy/*metabolism/pathology MH - Cell Death/drug effects MH - Coronary Vessels/drug effects/*metabolism/pathology MH - Homocysteine/blood/drug effects/*metabolism MH - Humans MH - Neuroprotective Agents/pharmacology OTO - NOTNLM OT - Methionine OT - endothelial dysfunction OT - homocysteine OT - hyperhomocysteinemia OT - inflammation OT - oxidative stress. EDAT- 2018/06/26 06:00 MHDA- 2019/11/22 06:00 CRDT- 2018/06/26 06:00 PHST- 2018/05/04 00:00 [received] PHST- 2018/06/04 00:00 [revised] PHST- 2018/06/14 00:00 [accepted] PHST- 2018/06/26 06:00 [pubmed] PHST- 2019/11/22 06:00 [medline] PHST- 2018/06/26 06:00 [entrez] AID - CPD-EPUB-91249 [pii] AID - 10.2174/1381612824666180625125450 [doi] PST - ppublish SO - Curr Pharm Des. 2018;24(25):2911-2920. doi: 10.2174/1381612824666180625125450.