Post by Max on Jun 13, 2005 18:11:57 GMT -5
Several clinical associtations to cardiovascular effects in human subjects exposed to (Ro)accutane
Hoffman la Roche itself has reported the following associations of cardiovascular effects in human subjects exposed to (Ro)accutane: palpitation, tachycardia, vascular thrombotic disease and even stroke [0]. There are several independent case reports of premature atrial beats and episodes of nonsustained atrial tachycardia and other associated cardiac effects [1 and more].
Several pathways involved both for direct interaction with cardiofunction and significantly increased predisposing risks in exposed human subjects, pathways for causal links
Significant serotonergic effects and significant effects on the angiotensin/renin system - significantly decreased AT-1 receptor expression and angiotensin II synthesis
5-HT receptor subtypes (5-HT1, 5-HT2, 5-HT3, 5-HT4 and 5-HT7) in brainstem regions are found to be involved in cardiac control [2]. 5-HT(1A) is suggested to be inhibited due to a significantly decreased promoter activity of Sp1 and NF-Y. TPH is inhibited due to a similiar effect, resulting in a lessened biosynthesis of serotonin. It is a possiblility that more 5-HT receptor isotypes than only 5-HT(1A) is heavily affected, thus affecting cardiac control.
Angiotensin II (ANG II) internalization in some tissues is suggested to be megalin dependent and it is suggested that megalin may play a role in regulating proximal tubule ANG II levels [3]. The megalin receptors are suggested to be heavily affected due to a decreased phosphorylation of Sp1.
Recent evidence indicates that EGF receptor transactivation by heparin-binding EGF (HB-EGF) contributes to hypertrophic signaling in cardiomyocytes. HB-EGF operates in a spatially restricted circuit in the extracellular space within the myocardium, revealing the critical nature of the local microenvironment in intercellular signaling [4]. In transgenic epidermis, dnRARalpha dose-dependently inhibited tRA induction of suprabasal HB-EGF and subsequent basal cell proliferation [7]. A similiar effect is suggested to affect cardiomyocytes, thus contributing to inhibit cell signaling.
The individual actions of Ang II on EGF-R transactivation in specific cell types are related to differential involvement of MMP-dependent HB-EGF release. Stimulation of the angiotensin II (Ang II) type 1 receptor (AT1-R) causes phosphorylation of extracellularly regulated kinases 1 and 2 (ERK1/2) via epidermal growth factor receptor (EGF-R) transactivation-dependent or -independent pathways in Ang II target cells [5]. In rats a massive dose all-trans-RA, comparable to what is seen in human acne-subjects, influences the renal RAS in anti-Thy1.1 nephritis by decreasing ANG II synthesis and receptor expression [6]. PPAR-gamma suppressed angiotensin II type 1 receptor (AT1R) gene transcription in vascular smooth muscle cells (VSMCs) by the inhibition of Sp1 binding to the --58/--34 GC-box related element in the AT1R gene promoter region via a protein-protein interaction [8].
(Ro)accutane induced CVD and CHF risk factors with age
The results from the ULSAM study, started in 1970, suggest that insulin resistance predicts congestive heart failure (CHF) both in middle-aged and elderly men, and thus is a clearly defined risk factor [9].
Hoffman la Roche itself has reported the following associations of cardiovascular effects in human subjects exposed to (Ro)accutane: palpitation, tachycardia, vascular thrombotic disease and even stroke [0]. There are several independent case reports of premature atrial beats and episodes of nonsustained atrial tachycardia and other associated cardiac effects [1 and more].
Several pathways involved both for direct interaction with cardiofunction and significantly increased predisposing risks in exposed human subjects, pathways for causal links
Significant serotonergic effects and significant effects on the angiotensin/renin system - significantly decreased AT-1 receptor expression and angiotensin II synthesis
5-HT receptor subtypes (5-HT1, 5-HT2, 5-HT3, 5-HT4 and 5-HT7) in brainstem regions are found to be involved in cardiac control [2]. 5-HT(1A) is suggested to be inhibited due to a significantly decreased promoter activity of Sp1 and NF-Y. TPH is inhibited due to a similiar effect, resulting in a lessened biosynthesis of serotonin. It is a possiblility that more 5-HT receptor isotypes than only 5-HT(1A) is heavily affected, thus affecting cardiac control.
Angiotensin II (ANG II) internalization in some tissues is suggested to be megalin dependent and it is suggested that megalin may play a role in regulating proximal tubule ANG II levels [3]. The megalin receptors are suggested to be heavily affected due to a decreased phosphorylation of Sp1.
Recent evidence indicates that EGF receptor transactivation by heparin-binding EGF (HB-EGF) contributes to hypertrophic signaling in cardiomyocytes. HB-EGF operates in a spatially restricted circuit in the extracellular space within the myocardium, revealing the critical nature of the local microenvironment in intercellular signaling [4]. In transgenic epidermis, dnRARalpha dose-dependently inhibited tRA induction of suprabasal HB-EGF and subsequent basal cell proliferation [7]. A similiar effect is suggested to affect cardiomyocytes, thus contributing to inhibit cell signaling.
The individual actions of Ang II on EGF-R transactivation in specific cell types are related to differential involvement of MMP-dependent HB-EGF release. Stimulation of the angiotensin II (Ang II) type 1 receptor (AT1-R) causes phosphorylation of extracellularly regulated kinases 1 and 2 (ERK1/2) via epidermal growth factor receptor (EGF-R) transactivation-dependent or -independent pathways in Ang II target cells [5]. In rats a massive dose all-trans-RA, comparable to what is seen in human acne-subjects, influences the renal RAS in anti-Thy1.1 nephritis by decreasing ANG II synthesis and receptor expression [6]. PPAR-gamma suppressed angiotensin II type 1 receptor (AT1R) gene transcription in vascular smooth muscle cells (VSMCs) by the inhibition of Sp1 binding to the --58/--34 GC-box related element in the AT1R gene promoter region via a protein-protein interaction [8].
(Ro)accutane induced CVD and CHF risk factors with age
The results from the ULSAM study, started in 1970, suggest that insulin resistance predicts congestive heart failure (CHF) both in middle-aged and elderly men, and thus is a clearly defined risk factor [9].