Subcellular changes in myocardial dysfunction in the diabetic heart

Danklle coulolnbe.

Feuvmy, Delphina Baetz, Physiologle ceilulain,

Lannelongue,

Unlvwait6

Soad Chattou, Akin omay a H&p. M.

Park Xl, Fmncr.

Recent results are consistent with the hypothesis that increases in intracellular-free Na’ concentrations (Na’i) during ischemia may ultimately lead to calcium overload and associated cellular damage. Besides attenuation of Na’ efflux, Na’ influx via Na*IH* exchange (NHE) and the

voltage-gated

represent the most plausible of Na’i Qain during ischemia. The depressed activity of NHE associated with ST&induced diabetes in rat ventricular myocytes has been proposed as underlying

channel

mechanisms

the mechanism the early phase activity during may also aeIve

for cardiaq protection, of reperfuaion’. However,

especially the role

during of NHE

ischemia is questioned*. The Na’ channels aa a route

for

iachemic

Na’

influx

after

myocytes become inexcitable. that lysophosphatidylcholine

Our recent results indicate (LPC), an amphipathic

metabolite

in the

which

accumulate

sarcolemma

during

ischemia, induces the development of a slowly inactlvating component of Na’ current, Iw,, in ventricular myocytes of normal and diabetic rats. This current Is Significantly decreased in myooyles from diabetic rat hearts. Furthermore, LPC-induced I,,& is significantly inhibited by the NHE blockers MEW, EIPAand HOEBQ. But, the sensitivity to inhlbition by HOE w and EPA is markedly reduced in diabetic ventricular myocytes, with no observed inhibition by HOE w. These data may have important implications as to the protection that may be afforded against ischemic and reperfusion injury, especially during ischemia diabetic situation. ‘Khandoudi et al. Diebetes %I Banani ei al. Canliovasc.

and when

ischemia

occurs

1995: 44: 196-202 Rei. 2000; 47: 688-696

SUBCELLULAR CHANGES IN MYOCARDIALDYSFWNC’l’TONINTHE DIABETICHEART Nobuakira B&e&. Dept. of General Medicine, Aoto Hospital, Jikei University School of Medicine, Tokyo, Japan Alterations in cardiac metabolism is one of the most Sreguent and profknd findings in diabetes mellitus. %ntxkular myosin isozyme pattern, for example, shifts to V3 predominant one in diabstic rata. This is a brief review of our recent studies concerning subcellular changes relating to cardiac metabolism in diabetes mellitus. In experimental diabetes induced by stremti in rate Ca-ATPase of sarcoplasmic n&iculum decreased and tbis can explain diastc~lic dyafuwtion in the diabetic heart. Changes in cardiac gene expression in mitochondrial energy metabolism was also examined. A152

in a

EFFECT OF HYPERGLYCEMIA ON MYOCYTE APOPTOSIS Stephen Schaffer and Viktoriya Solodushko. University Pharmacology,

of

South Alabama, Mobile, AL

Department

of

Chronic hyperglycemia preconditions the cardiomyocyte against hypoxic injury (Am J Physiol 278: H1948-1964, 2000). This csrdioprotective effect was bleed by incubating the cardiomyocyts with medium containing the protein kinase C (PKC) inhibitor, chelerythrine. The PKC inhibitor also prevented the glucose-induced upregulation of the anti-apoptotic factor, Bcl-2, and the inactivation of the pro-apoptotic factor, Bad. Like cheierythrine, angiotensin II was found to prevent the cardioprotsctive effects of chronic hyperglycemia while blocking the upregulation of Bcl-2. These effects of angiotensin II were associated with significant changes in the distribution of various PKC isoforms. In response to chronic hyperglycemia alone, several PKC isoforms, including PKCp2 and PKCG, were translated from the cytosolic fraction to the particulate fraction. The extent of PKC isoform redistribution was diminished in the presence of angiotsnsin II. Other isoforms, such as PKG. were upregulated by chronic hyperglycemia alone, but their distribution within the cell remained unaltered. Angiotensin II did not appear to significantly alter this pattern. The data implicate Bcl-2 and glucose-induced PKC translocation in the cardioprotectlve effscts of chronic hyperglycemia. The study was supported by a grant from the National Institutes of Health.

CARDIAC LIPOPROTEIN LIPASE:POSSIBLE ROLE IN DIABETIC CARDIOMYOPATHY Brian Rodrigues, Mohammed A. Abrahani, Nandakumar Sambandam and Osama Al-Atar. Fat. of Pharm. Sci., UBC, Van., BC. Aberrant substrate supply and utilization may play an important role in the development of heart disease during diabetes. In the heart, coronary endothelial LPL hydrolyzes lipoprotein triglyceride to FFA, which are transported into the heart for numerous metabolic functions. We have demonstrated, significantly elevated LPL activity in STZdiabetic rats, an outcome that was not secondary to an expanded cellular pool, which was dramatically reduced. More recently, we have confirmed that: a) the increase in LPL originates mainly in capillary blood vessels, presumably within or at the luminal and abluminal surface of the endothelial cell, b) the intravascular heparin-releasable fraction of cardiac LPL can be acutely (hours) regulated by short-term changes in insulin, c) the enlarged LPL pool is functionally relevant and is capable of hydrolyzing VLDL, and d) alterations in the transport and utilization of glucose likely modulate changes in cardiac LPL activity and thereby influence FFA consumption. The mechanism(s) underlying this abnormally high enzyme However, regulation at this activity is currently unclear. location is essential as increased cardiac LPL may be an important mechanism whereby the heart is able to maintain its function at time of metabolic stress characterized by inadequate glucose utilization. However, this mechanism could eventually become counterproductive as abnormally high LPL activity could provide excess FFA to the diabetic heart leading to a number of metabolic, morphological and mechanical changes, and eventually to cardiac disease. Supported by the CDA 8 the HSFBCIY